Controlled release drug dimers

ABSTRACT

The disclosure features pharmaceutical compositions formed from prodrug dimers for the extended delivery of a drug and for the treatment of a disease or condition.

CROSS-REFERENCES

This application claims the benefit of U.S. Provisional Application No.62/883,987, filed Aug. 7, 2019, and U.S. Provisional Application No.63/019,181, filed May 1, 2020, which are hereby incorporated byreference in their entirety herein.

BACKGROUND OF THE INVENTION

While the clinical importance of sustained drug release delivery systemsto maintain therapeutic concentration of drugs for extended periods oftime (e.g., days to weeks, to months, or even years) has been wellacknowledged for decades, there has been a limited number ofsuccessfully commercialized products on the market to date. To developsuccessful sustained drug delivery systems, technical difficulties mustbe overcome ranging from drug degradation during formulation process;lack of controlled release, including unwanted burst or incompleterelease associated with diffusion or bulk erosion mechanisms of drugrelease; low encapsulation efficiency; and formulation complexity.

For locally administered sustained release delivery systems, additionalchallenges can arise where the mass balance of the carrier or matrix forthe drug hinders drug loading, or where the carriers and matricesproduce unwanted effects (i.e., such as local inflammation).

There is an unmet need for a sustained release drug system that isformulated to release a drug via a surface erosion process in theabsence or with a minimal amount of carrier and/or excipient agents, ata rate-controlled manner over an extended period of time (e.g., days toweeks, to months, or even years), where the system containspredominantly drug and minimizes side effects associated with the use ofcarriers or matrices.

SUMMARY OF THE INVENTION

Provided in certain embodiments herein are compounds comprising a firstradical (D1) and a second radical (D2) (e.g., having the formula:D1-L-D2). In certain embodiments, L is a hydrolyzable linker, such thatwhen the compound of formula D1-L-D2 is (e.g., subcutaneously orintraspinal) administered (or when present in or otherwise exposed to anaqueous environment, such as a buffering solution, serum, or the like),D1 and D2 are released (e.g., in their free, non-radical form). Incertain instances, the (e.g., covalent) joining of a D1 and a D2 througha linker L provides a compound comprising a processable form.

In some instances, compounds provided herein are processable into forms(e.g., implants, coatings, or other bodies), such as that are capable ofbeing administered to an individual in need thereof. In some instances,such compounds are processable without the need for additionalexcipients or materials (e.g., controlled release polymers, matrices, orother components). In certain instances, the no or low amounts ofadditional excipients or materials facilitates high overall quantitiesof drug delivery (e.g., over an extended period), while limiting impactof drug delivery (e.g., a small implant can have high quantities ofdrug).

In certain instances, such compounds (or implants comprising suchcompounds) are administered to (e.g., implanted into) an individual,such that sustained and/or otherwise controlled (e.g., local orsystemic) delivery of the drug is achieved. In some instances, deliveryof the compounds (e.g., in the form of an implant, coating, etc.)facilitate delivery of a drug component or radical thereof for anextended period of time, such as for weeks, months, or more. In certaininstances, compounds, formulations, and implants provided hereinfacilitate the long term delivery of drugs to an individual in needthereof, such as without the need for frequent dosing. In someinstances, without rigid compliance to frequent administration isrequired to maintain (e.g., optimal) therapeutic efficacy. With thecompounds provided herein, however, long term delivery of such drugs canbe achieved from weeks, months, or more, with infrequent administration(e.g., once a year, twice a year, or the like).

Provided in certain embodiments herein are compounds, such as describedherein, (e.g., pharmaceutical) compositions comprising compoundsdescribed herein, and methods of making and using compounds providedherein. In some embodiments, methods of using the compounds providedherein include methods of treating disorders in individuals in needthereof, such as disorders treatable by a drugs D1 and/or D2 (e.g., inits free form). It is to be understood that disclosures of methodsprovided herein explicitly include disclosures of pharmaceuticalcompositions comprising (e.g., an effective amount) of a compoundprovided herein for such uses.

In certain embodiments, provided herein is a compound of a structure ofFormula (III):

D1-L-D2  (III)

wherein:

D1 is a first radical;

D2 is a second radical;

L is a (e.g., hydrolyzable) linker covalently linking D1 to D2,

or a pharmaceutically salt or solvate thereof,

wherein the first and second radicals are non-steroidal.

In some instances, D1 and/or D2 are attached to the linker through ahydroxyl radical, an amine radical, an amide radial, a carboxylateradical, or a thiol radical. In some embodiments, D1 and/or D2 areattached to the linker through a hydroxyl radical, an amine radical, ora carboxylate radical.

In some embodiments, the first radical and the second radical are eachindependently selected from a nonsteroidal anti-inflammatory drug(NSAID) (e.g., pranoprofen, bromfenac, and indoprofen), a CNS agent(e.g., an analgesic agent, an anti-psychotic agent (e.g., haloperidol),an anti-depressive agent, an anti-histamine, an anti-convulsant (e.g.,L-DOPA)), a rho kinase (ROCK) inhibitor (e.g., ripasudil and fasudil),an anthraquinone (e.g., diacerein), an anti-cancer agent (e.g.,podophyllotoxin, SN-38, and melphalan), an anti-viral agent (e.g.,trifluridine and podophyllotoxin), an anti-oxidant (e.g., ferulic acidand kaempferol), a muscarinic antagonist, an anti-microbial agent (e.g.,cefazolin and tedizolid), or an anti-coagulant (e.g., warfarin) in theirfree form.

In some embodiments, at least one of the first radical or the secondradical is a solid (e.g., at a temperature of less than or equal to 30°C.) in their free form. In certain instances, the first radical and thesecond radical are each a solid (e.g., at a temperature of less than orequal to 30° C.) in their free form.

In some embodiments, the compound has the structure of Formula (II-B):

wherein:

L is a linker,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of Formula (II-C):

wherein:

L is a linker,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of Formula (II-D):

wherein:

R^(m) and R^(m)′ are each independently H or optionally substitutedalkyl;

R^(n) and R^(n)′ are each independently H or optionally substitutedalkyl; and

L is a linker,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of Formula (II-E):

wherein:

R^(m) and R^(m)′ are each independently H or optionally substitutedalkyl;

R^(n) and R^(n)′ are each independently H or optionally substitutedalkyl;

R^(o) and R^(o)′ are each independently H or optionally substitutedalkyl; and

L is a linker,

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound has the structure of Formula (II-F):

wherein:

L is a linker,

or a pharmaceutically acceptable salt thereof.

In some embodiments, any one of R^(m), R^(n), or R^(o) is adjoined toany one of R^(m)′, R^(n)′, or R^(o)′ by the linker. In some embodiments,R^(m) is adjoined to R^(m)′ by the linker. In some embodiments, R^(n) isadjoined to R^(n)′ by the linker. In some embodiments, R^(o) is adjoinedto R^(o)′ by the linker.

In some embodiments, the linker is a hydrolyzable linker. In someembodiments, the hydrolyzable linker comprises one or more hydrolyzablegroup.

In some embodiments, the linker is alkyl (e.g., saturated alkyl orunsaturated alkyl), heteroalkyl, or alkoxy, wherein the alkyl,heteroalkyl, or alkoxy is optionally substituted. In some embodiments,the alkyl, heteroalkyl, or alkoxy are each independently substitutedwith one or more groups, each group being independently selected fromoxo, —O—, —S—, silicone, amino, alkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl or heteroaryl, wherein the alkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionallysubstituted. In some embodiments, the linker comprises one or morelinker groups, each linker group being independently selected from oxo,—O—, —S—, optionally substituted alkylene (e.g., alkenyl, alkynyl,branched (e.g., polypropylene), haloalkyl), optionally substitutedheteroalkylene (e.g, polyTHF), and optionally substituted cycloalkylene.In some embodiments, the linker comprises one or more linker groups,each linker group being independently selected from alkyl, alkoxy, andcycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl are optionallysubstituted. In some embodiments, the linker comprises one or morelinker groups selected from oxo, —O—, —S—, unsubstituted alkylene,(CH₂CH₂)_(n), (CHCH)_(n), O(CH₂CH₂O)_(n), (CH₂CH₂O)_(n), and(CH(CH₃)C(═O)O)_(n), wherein n is 1-20. In some embodiments, the linkercomprises one or more linker group selected from oxo, unsubstitutedalkylene, (CH₂CH₂)_(n), (CHCH)_(n), O(CH₂CH₂O)_(n), (CH₂CH₂O)_(n),(CH(CH₃)C(═O)O)_(n), or (CH₂CH₂)_(n)C═O(CH(CH₃)C(═O)O)_(n), wherein n is1-20. In some embodiments, the linker is alkyl (alkylene) substitutedwith one or more groups selected from —OH, halo, oxo, alkyl,heteroalkyl, cycloalkyl, and heterocycloalkyl. In some embodiments, thelinker is unsubstituted alkyl (alkylene). In some embodiments, thelinker is heteroalkyl (heteroalkylene) substituted with one or moregroups selected from halo or alkyl. In some embodiments, the linker isunsubstituted heteroalkyl (heteroalkylene). In some embodiments, thelinker is selected from the group consisting of: —(CR₂)_(y)—,—(C═O)(CR₂)_(y)(C═O)—, —O(CR₂)_(y)O—, —(C═O)O(CR₂)_(y)O(C═O)—,—O(CR₂)_(y)—, —(CR₂)_(y)O—, and —O(CH₂CH₂O)_(y)—, wherein y is 1-10 andeach R is independently selected from the group consisting of H,halogen, alkyl, or is taken together with another R to form anoptionally substituted cycloalkyl.

In some embodiments, the linker is hydrolyzed in a buffered solution. Insome embodiments, the linker is hydrolyzed by an enzyme. In someembodiments, the enzyme is a hydrolase (e.g., a protease or anesterase).

In some embodiments, the compound is processable (e.g., into an articleor the amorphous state). In some embodiments, the compound is a solid(e.g., has a melting point (e.g., T_(m) or T_(g)) of at least 37° C.).In some embodiments, the compound is a crystalline solid, a film, aglass, or an amorphous solid (e.g., at a temperature of at least 37°C.). In some embodiments, the compound has crystallinity of at most 15%(e.g., determined by PXRD, DSC, or polarized light microscopy). In someembodiments, the compound is substantially not crystalline (e.g.,determined by PXRD, DSC, or polarized light microscopy). In someembodiments, the compound is amorphous (e.g., determined by PXRD, DSC,or polarized light microscopy). In some embodiments, the thermal meltingpoint (T_(m)) is greater than or equal to the glass transitiontemperature (T_(g)). In some embodiments, the compound has a meltingpoint of at least 37° C. In some embodiments, the compound has a meltingpoint of at least 100° C.

Provided in some embodiments herein are drug dimers and articles formedfrom the drug dimers. In some embodiments, the articles are machined,molded, emulsion-processed, electrospun, electrosprayed, blow molded,fiber spun (e.g., wet spun, dry spun, melt spun, heat spun, or gelspun), or extruded to form a fiber, fiber mesh, woven fabric, non-wovenfabric, film, surface coating, pellet, cylinder, microparticle (e.g., amicrobead), nanoparticle (e.g., a nanobead), or any other type shapedarticle (e.g., from which the prodrug drug dimer is released in acontrolled fashion).

In certain embodiments, the article comprises a compound of formula(A-I):

D1-L-D2  (A-I)

or a pharmaceutically acceptable salt thereof, wherein (i) each of D1and D2 is, independently, a radical formed from a drug bearing ahydroxyl, primary amino, secondary amino, enolizable ketone, or carboxylfunctional group for covalent attachment to L; and L is a linkercovalently linking D1 to D2, and (ii) at least 70% (w/w) (e.g., 75±5%,80±5%, 85±5%, 90±5%, or 95±5% (w/w)) of the article is the compound offormula (A-I), and wherein D1 and D2 are not radicals formed from asteroid.

In some embodiments, the article is a fiber, fiber mesh, woven fabric,non-woven fabric, film, surface coating, pellet, cylinder, hollow tube,microparticle, nanoparticle, or shaped article. In some embodiments, thecompound, D1, or D2 are released from the article through surfaceerosion. In certain embodiments, the article is free of controlledrelease polymer. In particular embodiments, D1 and D2 are released fromthe article at 37° C. in 100% bovine serum or at 37° C. in PBS at a ratesuch that t₁₀ is greater than or equal to 1/10 of t₅₀.

In some embodiments, provided herein is a method of forming or producingan article provided herein. In some embodiments, the method comprises(a) heating the compound (e.g., a crystalline form (e.g., a solid or apowder)), or a pharmaceutically acceptable salt thereof, (e.g., to forma melt or a glass); and (b) (e.g., heat) molding the compound (e.g., themelt or glass) to form the article. In some embodiments, the methodcomprises (a) heating the compound, or a pharmaceutically acceptablesalt thereof, (e.g., to form a melt or a glass); and (b) (e.g.,injection or blow) molding the compound (e.g., the melt or the glass) toform the article. In some embodiments, the method comprises (a)dissolving the compound, or a pharmaceutically acceptable salt thereof,in a solvent (e.g., to form a solution); and (b) evaporating the solventto form the article. For example, step (b) can include solvent castingto form a film or a fiber. In some embodiments, the method comprises (a)dissolving the compound, or a pharmaceutically acceptable salt thereof,in a solvent (e.g., to form a solution); and (b) electrospinning orelectrospraying the solution to form the article. In some embodiments,the method comprises (a) heating the compound, or a pharmaceuticallyacceptable salt thereof, (e.g., to form a melt or a glass); and (b)electrospinning or electrospraying the compound (e.g., the melt or theglass) to form the article. In some embodiments, the method comprises(a) heating the compound, or a pharmaceutically acceptable salt thereof,(e.g., to form a melt); (b) extruding the compound (e.g., the melt orthe glass) to form the article. In some embodiments, the article isfurther annealed.

In certain embodiments, at least 70% (w/w) of the article is a compoundof formula (A-I), e.g., at least 75% (w/w), at least 80% (w/w), at least85% (w/w), at least 90% (w/w), at least 95% (w/w), or at least 99%(w/w).

In another embodiment, the compound is released from the article throughsurface erosion. In certain embodiments, release from the article (e.g.,through surface erosion) is less than 20% (e.g., less than 18%, 15%,12%, 10%, or 5%) of D1 or D2 ((e.g. as a percentage of the total drug,D1 or D2, present in the article in prodrug form) e.g., at 37° C. in100% bovine serum over 5 days, 6 days, 7 days, 8 days, 9 days, 10 days,or 12 days (e.g., less than 10% of D1 or D2 at 37° C. in 100% bovineserum over 5 days)). In other embodiments, release from the article(e.g., through surface erosion) is less than 2.0% (e.g., less than 1.8%,1.5%, 1.2%, 1.0%, or 0.5%) of D1 or D2 ((e.g., as a percentage of thetotal drug, D1 or D2, present in the article in prodrug form) e.g., at37° C. in PBS over 5 days, 7 days, 10 days, or 14 days (e.g., less than2% of D1 or D2 at 37° C. in PBS over 5 days)). In still otherembodiments, release from the article (e.g., through surface erosion)releases greater than 20% (e.g., greater than 22%, 24%, 26%, 28%, or30%) of D1 or D2 ((e.g., as a percentage of the total drug, D1 or D2,present in the article in prodrug form) e.g., at 37° C. in 100% bovineserum over not fewer than 6 days, 8 days, 10 days, or 12 days (e.g.,greater than 24% of D1 or D2 at 37° C. in 100% bovine serum over 10days)). In other embodiments, release from the article (e.g., throughsurface erosion) releases greater than 5.0% (e.g., greater than 6.0%,8.0%, 10%, 12%, or 15%) of D1 or D2 ((e.g., as a percentage of the totaldrug, D1 or D2, present in the article in prodrug form) e.g., at 37° C.in PBS over not fewer than 6 days, 8 days, 10 days, or 12 days (e.g.,greater than 5% of D1 or D2 at 37° C. in PBS over 10 days)). Thecompound (D1 and/or D2) can be released from the article at a rate suchthat t₁₀ is greater than or equal to 1/10 of t₅₀.

In some embodiments, the compound is provided by the formula (A-II):

D1-O-L-O-D2  (A-II),

or a pharmaceutically acceptable salt thereof, wherein each of D1-O andD2-O is, independently, a radical formed from a drug bearing a hydroxylfunctional group; L is —C(O)—(R^(A))—C(O)— or—C(O)—O—(R^(A))—O—C(O)—; R^(A) is selected from C₁₋₂₀ alkylene, a linearor branched heteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, acyclic system of 3 to 10 atoms, or O—(R^(A))—O is a radical of a polyoland includes at least one free hydroxyl group or is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. In some embodiments, each        of D1-O and D2-O is, independently, formed from morphine,        oxycodone, podophyllotoxin, SN-38, trifluridine, kaempferol,        tedizolid, warfarin, resveratrol, epinephrine, naloxone,        forskolin, doxorubicin, erythromycin, etoposide, sirolimus,        phenytoin, DL-atenolol, thalidomide, acetazolamide, chloroxine,        stavudine, sulfacetamide, meloxicam, salbutamol, haloperidol,        zileuton, piroxicam, primidone, (−)-chloramphenicol, cladribine,        chlortalidone, losartan, L-methyldopa, mitoxantrone, carbidopa,        dicoumarol, pindolol, (E)-entacapone, hydroxyzine, propranolol,        amoxicillin, cefdinir, labetalol, pemetrexed, digoxin, abacavir,        metirosine, cefradine, nelarabine, lorazepam, isoprenaline,        oxazepam, daunorubicin, fenamisal, misoprostol, naltrexone,        (−)-S-timolol, miglustat, tetracycline, (+)-tramadol, digitoxin,        spectinomycin, masoprocol, levobunolol, chlortetracycline,        novobiocin, ergotamine, rifaximin, (−)-oxymorphone,        methysergide, cefmenoxime, cefaloglycin, or nitroxoline. The        moiety O—(R^(A))—O can be a radical of a polyol formed from a        cyclitol, a sugar alcohol, a linear or cyclic alkane diol, or        glycerin. In particular embodiments, O—(R^(A))—O is a radical        formed from an alkane diol, diethylene glycol, triethylene        glycol, tetraethylene glycol, or pentaethylene glycol.

In certain embodiments, the compound comprises the structure of formula(A-III):

D1-C(O)-L-C(O)-D2  (A-III),

or a pharmaceutically acceptable salt thereof, wherein each of D1-C(O)and D2-C(O) is, independently, a radical formed from a drug bearing acarboxyl functional group; L is —O—(R^(A))—O—,—O—C(O)—O—(R^(A))—O—C(O)—O—, or —NH—(R^(A))—NH—; R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. In some embodiments, each        of D1-C(O) and D2-C(O) is, independently, formed from        pranoprofen, bromfenac, indoprofen, L-DOPA, diacerein,        melphalan, ferulic acid, cefazolin, flutathione, methotrexate,        indomethacin, furosemide, naproxen, nalidixic acid, baclofen,        bumetanide, amlexanox, L-Methyldopa, lisinopril, carbidopa,        D-(−)-ampicillin, cefalotin, cetirizine, amoxicillin, cefdinir,        metirosine, nedocromil, cefixime, piperacillin, ceforanide,        cefuroxime, gabapentin, benazeprilat, or ketorolac. The moiety        O—(R^(A))—O can be a radical of a polyol formed from a cyclitol,        a sugar alcohol, a linear or cyclic alkane diol, or glycerin. In        particular embodiments, O—(R^(A))—O is a radical formed from an        alkane diol, diethylene glycol, triethylene glycol,        tetraethylene glycol, or pentaethylene glycol.

In some embodiments, the compound comprises the structure of formula(A-IV):

D1-NH—C(O)-L-C(O)—NH-D2  (A-IV),

or a pharmaceutically acceptable salt thereof, wherein each of D1-NH andD2-NH is, independently, a radical formed from a drug bearing a primaryamino functional group; L is —O—(R^(A))—O— or —(R^(A))—; R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅-10 arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. In an alternative        embodiment of any of the above articles, the compound is        described by the formula (A-V):

or a pharmaceutically acceptable salt thereof, wherein each of

is, independently, a radical formed from a drug bearing a secondaryamino functional group; L is —O—(R^(A))—O— or —(R^(A))—; R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. In these embodiments, the        moiety O—(R^(A))—O can be a radical of a polyol formed from a        cyclitol, a sugar alcohol, a linear or cyclic alkane diol, or        glycerin. In particular embodiments, O—(R^(A))—O is a radical        formed from an alkane diol, diethylene glycol, triethylene        glycol, tetraethylene glycol, or pentaethylene glycol.

In some embodiments, the compound comprises the structure of formula(A-VI):

D1-N═C(R¹)-L-C(R¹)═NH-D2  (A-VI),

or a pharmaceutically acceptable salt thereof, wherein each of D1-N andD2-N is, independently, a radical formed from a drug bearing a primaryamino functional group; R¹ is a H or C₁₋₄ alkyl; L is —(R^(A))—; andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms.

I In some embodiments, the compound comprises the structure of formula(A-VII):

D1-NH-L-NH-D2  (A-VII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-N andD2-N is, independently, a radical formed from a drug bearing a primaryamino functional group; and L is —CH₂—O—(R^(A))—O—CH₂—,—CH(CH₃)—O—(R^(A))—O—CH(CH₃)—; and R^(A) is selected from C₁₋₂₀alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linearor branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀ alkynylene, aC₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, or O—(R^(A))—O is aradical of a polyol and includes at least one free hydroxyl group orO—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. In some embodiments, each        radical of the drug bearing the secondary amino functional group        or the drug bearing a primary amino functional group is,        independently, formed from epinephrine, trifluridine, mitomycin        C, fluorouracil, glutathione, doxorubicin, methotrexate,        nifedipine, prazosin, bromidinidine, trimethoprim, theophylline,        carbamazepine, sulfamethoxazole, omeprazole, furosemide,        tiabendazole, hydrochlorothiazide, DL-atenolol, dapsone,        pyrimethamine, albendazole, sulfadiazine, acetazolamide,        lamotrigine, sulfapyridine, lansoprazole, zonisamide,        azathioprine, valdecoxib, imiquimod, baclofen, sulfacetamide,        bumetanide, salbutamol, oxcarbazepine, torasemide,        sulfafurazole, zileuton, tadalafil, topamax, mafenide,        famotidine, indapamide, cladribine, chlortalidone, adefovir        dipivoxil, amlexanox, felbamate, isradipine, amoxapine,        clozapine, brimonidine, sulfamethoxydiazine, metolazone,        (E)-nitrofurazone, ILosartan, L-methyldopa, lisinopril,        hydroflumethiazide, dofetilide, minoxidil, nepafenac,        mitoxantrone, carbidopa, sulfamethizole, pindolol, primaquine,        D-(−)-ampicillin, diclofenamide, melphalan, sulfaphenazole,        bupropion, (E)-nizatidine, propranolol, sumatriptan,        amoxicillin, cefdinir, labetalol, valaciclovir, pemetrexed,        abacavir, metirosine, amiloride, cefradine, nelarabine,        (E)-dacarbazine, bendroflumethiazide, methyclothiazide,        isoprenaline, ethoxzolamide, daunorubicin, fenamisal, cefixime,        benzthiazide, dorzolamide, (−)-S-timolol, tocainide, neptazane,        tetracycline, guanfacine, trimetrexate, spectinomycin,        methylphenidate, levobunolol, guanethidine, cyclothiazide,        guanabenz, chlortetracycline, novobiocin, polythiazide,        ergotamine, acetylsulfafurazole, ceforanide, quinethazone,        sulfacytine, cefmenoxime, cefaloglycin, cefuroxime, gabapentin,        benazeprilat, tamsulosin, ripasudil, or fasudil.

In some embodiments, the compound comprises the structure of formula(A-VIII):

D1-E-L-E-D2  (A-VIII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-E andD2-E is, independently, a radical formed from a drug bearing anenolizable ketone functional group (i.e., a ketone adjacent a C—H groupthat together permit an enol tautomerization); L is —C(O)—(R^(A))—C(O)—or—C(O)—O—(R^(A))—O—C(O)—; R^(A) is selected from C₁₋₂₀ alkylene, a linearor branched heteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, acyclic system of 3 to 10 atoms, or O—(R^(A))—O is a radical of a polyoland comprises at least one free hydroxyl group or is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10.

In some embodiments, L has a molecular weight of from 80 to 800 Da,e.g., 80 to 100 Da, 80 to 200 Da, 80 to 300 Da, 80 to 400 Da, 80 to 500Da, 80 to 600 Da, or 80 to 700 Da. In another embodiment of any of theabove articles, L is covalently linked to D1 and to D2 via one or moreester, carbonate, carbonate ester, or anhydride linkages. In certainembodiments, L is covalently linked to D1 and to D2 via one or morecarbonate linkages. In certain embodiments, L is covalently linked to D1and D2 via one or more amide or carbamate linkages. In some embodiments,L is covalently linked to D1 and D2 via one or more imine linkages.

In some embodiments, each of D1 and D2 is selected from a nonsteroidalanti-inflammatory drug (NSAID), an analgesic, a CNS agent, a rho kinase(ROCK) inhibitor, an anthraquinone, an anti-cancer agent, an antiviralagent, an antioxidant, a muscarinic antagonist, an antimicrobial agent,and an anticoagulant.

In certain embodiments, the compound is further described by any one offormulas (II)-(IV), (IX)-(XXXIV), and (XLII)-(XLIV). In anotherembodiment of any of the above articles, each of D1 and D2 is,independently, described by any one of formulas (I-e)-(I-v), and(I-y)-(I-ax), described herein.

In the articles of the disclosure, D1 and D2 can be formed from the samedrug, or D1 and D2 can be formed from different drugs.

In other embodiments, the article is free of controlled release polymer,free of a crystallization inhibiting excipient, free of a mechanicalintegrity enhancing excipient; and/or free of a binding excipient.

In a particular embodiment of any of the above articles, the article hasa glassy state. The glassy state composition can be formed by machining,molding, fiber spinning, electrospinning, electrospraying, blow molding,or extruding methods.

In certain embodiments, the article is a fiber, fiber mesh, wovenfabric, non-woven fabric, film, surface coating, pellet, cylinder,hollow tube, microparticle, nanoparticle, or shaped article. The fibersof the invention can be used to form articles in the form of a fibermesh, non-woven fabric, or woven fabric.

In other embodiments, the article is a glassy state fiber having a meandiameter of from about 0.01 to 1 mm, e.g., 0.05 to 0.3 mm, 0.1 to 0.3mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm, 0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01to 0.2 mm, 0.01 to 0.3 mm, 0.01 to 0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm, or 0.01 to 0.9 mm. In someembodiments, a mean length of the fiber can range from about 20 mm to 20meters, e.g., 20 to 100 mm, 75 to 300 mm, 100 mm to 1 meter, 0.5 metersto 6 meters, or 1.0 meters to 20 meters.

In certain embodiments, the article is a glassy state pellet having amean diameter of from about 0.2 to 5 mm, e.g., from about 0.2 to 1 mm,from about 0.2 to 2 mm, from about 0.3 to 3 mm, from about 1.5 to 5 mm,from about 2 to 5 mm, from about 2.5 to 5 mm, from about 3 to 5 mm, fromabout 3.5 to 5 mm, from about 4 to 5 mm, or from about 4.5 to 5 mm.

In some embodiments, the article is a glassy state cylinder of fromabout 0.5 to 20 mm in length, e.g., about to 0.5 to 1 mm, about 0.5 to 2mm, about 0.5 to 4 mm, about 0.5 to 6 mm, about 0.5 to 8 mm, about 0.5to 10 mm, about 0.5 to 12 mm, about 0.5 to 14 mm, about 0.5 to 16 mm, orabout 0.5 to 18 mm. In some embodiments, the article is in the form ofglassy state cylinders of from about 0.01 to 1 mm diameter, e.g., about0.1 to 0.2 mm, about 0.1 to 0.3 mm, about 0.1 to 0.4 mm, about 0.2 to0.5 mm, about 0.1 to 0.6 mm, about 0.1 to 0.7 mm, about 0.1 to 0.8 mm,or about 0.1 to 0.9 mm. In some embodiments, the mean diameter of thecylinder is in the range of about 0.01 to 1 mm and the mean length ofthe cylinder is about 0.1 mm to 4.0 mm. In some embodiments, the lengthof the cylinder is about 0.5 to 10 mm, or about 1 to 10 mm.

In some embodiments, the article is mechanically stable. For example,the article is resistant to breaking under deformation.

In other embodiments, the article is a glassy state microparticle, e.g.,microbead, having a mean diameter of from about 1 to 1000 μm, e.g.,about 10 to 1000 μm, about 100 to 1000 μm, about 200 to 1000 μm, about500 to 1000 μm, about 700 to 1000 μm, or about 900 to 1000 μm.

In certain embodiments, the article is a glassy state nanoparticle,e.g., nanobead, having a mean diameter of from about 0.01 to 1 μm, e.g.,about 0.05 to 1 μm, about 0.1 to 1 μm, about 0.2 to 1 μm, about 0.3 to 1μm, about 0.4 to 1 μm, about 0.5 to 1 μm, about 0.6 to 1 μm, about 0.7to 1 μm, about 0.8 to 1 μm, or about 0.9 to 1 μm.

In particular embodiments, the glassy state composition is a surfacecoating.

In certain instances, provided herein is an implantable medical devicecomprising a surface coating (e.g., or article) provided herein. In someembodiments, the coating resides on the surface of the implantablemedical device.

In some embodiments, the compound comprises the structure of formula(A-II):

D1-O-L-O-D2  (A-II),

or a pharmaceutically acceptable salt thereof, wherein each of D1-O andD2-O is, independently, a radical formed from a drug bearing a hydroxylfunctional group; L is —C(O)—(R^(A))—C(O)— or—C(O)—O—(R^(A))—O—C(O)—; R^(A) is selected from C₁₋₂₀ alkylene, a linearor branched heteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, acyclic system of 3 to 10 atoms, or O—(R^(A))—O is a radical of a polyoland includes at least one free hydroxyl group or is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. In some embodiments, each        of D1-O and D2-O is, independently, formed from morphine,        oxycodone, podophyllotoxin, SN-38, trifluridine, kaempferol,        tedizolid, warfarin, resveratrol, epinephrine, naloxone,        forskolin, doxorubicin, erythromycin, etoposide, sirolimus,        phenytoin, DL-atenolol, thalidomide, acetazolamide, chloroxine,        stavudine, sulfacetamide, meloxicam, salbutamol, haloperidol,        zileuton, piroxicam, primidone, (−)-chloramphenicol, cladribine,        chlortalidone, losartan, L-methyldopa, mitoxantrone, carbidopa,        dicoumarol, pindolol, (E)-entacapone, hydroxyzine, propranolol,        amoxicillin, cefdinir, labetalol, pemetrexed, digoxin, abacavir,        metirosine, cefradine, nelarabine, lorazepam, isoprenaline,        oxazepam, daunorubicin, fenamisal, misoprostol, naltrexone,        (−)-S-timolol, miglustat, tetracycline, (+)-tramadol, digitoxin,        spectinomycin, masoprocol, levobunolol, chlortetracycline,        novobiocin, ergotamine, rifaximin, (−)-oxymorphone,        methysergide, cefmenoxime, cefaloglycin, or nitroxoline. The        moiety O—(R^(A))—O can be a radical of a polyol formed from a        cyclitol, a sugar alcohol, a linear or cyclic alkane diol, or        glycerin. In particular embodiments, O—(R^(A))—O is a radical        formed from an alkane diol, diethylene glycol, triethylene        glycol, tetraethylene glycol, or pentaethylene glycol.

In some embodiments, the compound comprises the structure of formula(A-III):

D1-C(O)-L-C(O)-D2  (A-III),

or a pharmaceutically acceptable salt thereof, wherein each of D1-C(O)and D2-C(O) is, independently, a radical formed from a drug bearing acarboxyl functional group; L is —O—(R^(A))—O—,—O—C(O)—O—(R^(A))—O—C(O)—O—, or —NH—(R^(A))—NH—; R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

—O(CH₂CH₂O)_(n)CH₂CH₂O—,

—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or

—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and

n, m, and p are integers from 1 to 10. In some embodiments, each ofD1-C(O) and D2-C(O) is, independently, formed from pranoprofen,bromfenac, indoprofen, L-DOPA, diacerein, melphalan, ferulic acid,cefazolin, flutathione, methotrexate, indomethacin, furosemide,naproxen, nalidixic acid, baclofen, bumetanide, amlexanox, L-methyldopa,lisinopril, carbidopa, D-(−)-ampicillin, cefalotin, cetirizine,amoxicillin, cefdinir, metirosine, nedocromil, cefixime, piperacillin,ceforanide, cefuroxime, gabapentin, benazeprilat, or ketorolac. Themoiety O—(R^(A))—O can be a radical of a polyol formed from a cyclitol,a sugar alcohol, a linear or cyclic alkane diol, or glycerin. Inparticular embodiments, O—(R^(A))—O is a radical formed from an alkanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, orpentaethylene glycol.

In some embodiments, the compound comprises the structure of formula(A-IV):

D1-NH—C(O)-L-C(O)—NH-D2  (A-IV),

or a pharmaceutically acceptable salt thereof, wherein each of D1-NH andD2-NH is, independently, a radical formed from a drug bearing a primaryamino functional group; L is —O—(R^(A))—O— or —(R^(A))—; R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10.

In some embodiments, the compound comprises the structure of formula(A-V):

or a pharmaceutically acceptable salt thereof, wherein each of

is, independently, a radical formed from a drug bearing a secondaryamino functional group; L is —O—(R^(A))—O— or —(R^(A))—; R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. In these embodiments, the        moiety O—(R^(A))—O can be a radical of a polyol formed from a        cyclitol, a sugar alcohol, a linear or cyclic alkane diol, or        glycerin. In particular embodiments, O—(R^(A))—O is a radical        formed from an alkane diol, diethylene glycol, triethylene        glycol, tetraethylene glycol, or pentaethylene glycol.

In some embodiments, the compound comprises the structure of formula(A-VI):

D1-N═C(R¹)-L-C(R¹)═NH-D2  (A-VI),

or a pharmaceutically acceptable salt thereof, wherein each of D1-N andD2-N is, independently, a radical formed from a drug bearing a primaryamino functional group; R¹ is a H or C₁₋₄ alkyl; L is —(R^(A))—; andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms.

In some embodiments, the compound comprises the structure of formula(A-VII):

D1-NH-L-NH-D2  (A-VII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-N andD2-N is, independently, a radical formed from a drug bearing a primaryamino functional group; and L is —CH₂—O—(R^(A))—O—CH₂—,—CH(CH₃)—O—(R^(A))—O—CH(CH₃)—; and R^(A) is selected from C₁₋₂₀alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linearor branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀ alkynylene, aC₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, or O—(R^(A))—O is aradical of a polyol and includes at least one free hydroxyl group orO—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10.

In some embodiments, each radical of the drug bearing the secondaryamino functional group or the drug bearing a primary amino functionalgroup is, independently, formed from epinephrine, trifluridine,mitomycin C, fluorouracil, glutathione, doxorubicin, methotrexate,nifedipine, prazosin, bromidinidine, trimethoprim, theophylline,carbamazepine, sulfamethoxazole, omeprazole, furosemide, tiabendazole,hydrochlorothiazide, DL-atenolol, dapsone, pyrimethamine, albendazole,sulfadiazine, acetazolamide, lamotrigine, sulfapyridine, lansoprazole,zonisamide, azathioprine, valdecoxib, imiquimod, baclofen,sulfacetamide, bumetanide, salbutamol, oxcarbazepine, torasemide,sulfafurazole, zileuton, tadalafil, topamax, mafenide, famotidine,indapamide, cladribine, chlortalidone, adefovir dipivoxil, amlexanox,felbamate, isradipine, amoxapine, clozapine, brimonidine,sulfamethoxydiazine, metolazone, (E)-nitrofurazone, ILosartan,L-methyldopa, lisinopril, hydroflumethiazide, dofetilide, minoxidil,nepafenac, mitoxantrone, carbidopa, sulfamethizole, pindolol,primaquine, D-(−)-ampicillin, diclofenamide, melphalan, sulfaphenazole,bupropion, (E)-nizatidine, propranolol, sumatriptan, amoxicillin,cefdinir, labetalol, valaciclovir, pemetrexed, abacavir, metirosine,amiloride, cefradine, nelarabine, (E)-dacarbazine, bendroflumethiazide,methyclothiazide, isoprenaline, ethoxzolamide, daunorubicin, fenamisal,cefixime, benzthiazide, dorzolamide, (−)-S-timolol, tocainide,neptazane, tetracycline, guanfacine, trimetrexate, spectinomycin,methylphenidate, levobunolol, guanethidine, cyclothiazide, guanabenz,chlortetracycline, novobiocin, polythiazide, ergotamine,acetylsulfafurazole, ceforanide, quinethazone, sulfacytine, cefmenoxime,cefaloglycin, cefuroxime, gabapentin, benazeprilat, tamsulosin,ripasudil, or fasudil.

Th In some embodiments, the compound comprises the structure of formula(A-VIII):

D1-E-L-E-D2  (A-VIII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-E andD2-E is, independently, a radical formed from a drug bearing anenolizable ketone functional group (i.e., a ketone adjacent a C—H groupthat together permit an enol tautomerization); L is —C(O)—(R^(A))—C(O)—or—C(O)—O—(R^(A))—O—C(O)—; R^(A) is selected from C₁₋₂₀ alkylene, a linearor branched heteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, acyclic system of 3 to 10 atoms, or O—(R^(A))—O is a radical of a polyoland comprises at least one free hydroxyl group or is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10.

In certain instances, L has a molecular weight of from 80 to 800 Da,e.g., 80 to 100 Da, 80 to 200 Da, 80 to 300 Da, 80 to 400 Da, 80 to 500Da, 80 to 600 Da, or 80 to 700 Da. In another embodiment of any of theabove compounds, L is covalently linked to D1 and to D2 via one or moreester, carbonate, carbonate ester, or anhydride linkages. In particularembodiments, L is covalently linked to D1 and to D2 via one or morecarbonate linkages. In other embodiments, L is covalently linked to D1and D2 via one or more amide or carbamate linkages. In some embodiments,L is covalently linked to D1 and D2 via one or more imine linkages.

In some embodiments, each of D1 and D2 is selected from a nonsteroidalanti-inflammatory drug (NSAID), an analgesic, a CNS agent, a rho kinase(ROCK) inhibitor, an anthraquinone, an anti-cancer agent, an antiviralagent, an antioxidant, a muscarinic antagonist, an antimicrobial agent,and an anticoagulant.

In some embodiments, the compound is further described by any one offormulas (II)-(IV), (IX)-(XXXIV), and (XLII)-(XLIV). In someembodiments, each of D1 and D2 is, independently, described by any oneof formulas (I-e)-(I-v), and (I-y)-(I-ax), provided herein.

In some embodiments, either one or both of the first and/or secondradicals are released (e.g., in their free form), the release beingsustained release and/or extended release. In some embodiments, eitherone or both of the first and/or second radicals being released (e.g., intheir free form) for at least 14 days (e.g., in solution, buffersolution, serum, biological environment, in vivo, or the like).

In certain embodiments, provided herein is a pharmaceutical implant orcoating comprising any compound provided herein, or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the implant or coating comprises at least 50 wt. %(at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, at least 90wt. %, at least 95 wt. %, at least 98 wt. %, or the like) of thecompound and/or pharmaceutically acceptable salt thereof.

In some embodiments, the implant or coating undergoes surface erosion torelease the compound, the first radical, and/or the second radical. Insome embodiments, the first radical and the second radical are releasedfrom the pharmaceutical implant or coating at near zero-order in abuffered solution or in vivo. In some embodiments, the first radical andthe second radical are released from the pharmaceutical implant orcoating at 37° C. in 100% bovine serum or at 37° C. in phosphatebuffered saline (PBS) at a rate such that t₁₀ is greater than or equalto 1/10 of t₅₀.

Articles provided herein can be formed by (a) heating a compound offormula (A-I) above its melting point (e.g., depending upon thecompound, heating to 110-145° C., 130-185° C., 150-215° C., or 180-240°C.) to form a melt, and (b) cooling the melt to form an article. Thearticle can be shaped during step (a), prior to cooling, by pressing themelt into a mold, by extruding the melt from an orifice (e.g., to form acylinder or another shape), or by forming droplets of the melt andallowing the droplets to cool into glassy state droplets. Fibers can beformed by spinning (e.g. melt spinning, heat spinning, orelectrospinning), or pulling the melt (e.g., with tweezers) at differentrates to yield glassy state fibers of different diameters.

Alternatively, articles provided herein can be formed by (a) dissolvinga compound of formula (A-I) in a volatile organic solvent (e.g.,acetone, methanol, dichloromethane, tetrahydrofuran, chloroform, ormixtures thereof) to form a solution, and (b) removing the organicsolvent to form an article. The article can be shaped during step (b),prior to completely removing the organic solvent, by electrospraying,electrospinning, or fiber spinning the solution. For example, a 50:50v/v mixture of dichloromethane/tetrahydrofuran at 100% wt/v solution ofthe compound can be loaded at a rate of 0.5 mL/h and electrospun onto acylindrical mandrel rotating at 1150 rpm, forming aligned glassy statefibers. Fibers can be also formed by wet, dry, or gel spinning to formglassy state fibers of different diameters. Microparticles can beprepared by electrospraying a solution containing the compound at aconcentration of about 20% to 40% w/v or 25% to 50% w/v of the solution.Nanoparticles can be prepared by electrospraying a solution containingthe compound at a concentration of about 3% to 15% w/v or 5% to 18% w/vof the solution. Alternatively, a shaped article can be formed byplacing the solution in a mold and evaporating the volatile organicsolvent to form a shaped article.

Provided herein is a method of making an article provided hereincomprising: (a) heating the compound of formula (A-I), or apharmaceutically acceptable salt thereof, to form a melt; (b) coolingthe melt to form a glassy state composition; and (c) heating the glassystate composition to a temperature above the glass transitiontemperature of the glassy state composition and shaping the glassy statecomposition to form a shaped article.

Provided herein is a method of making an article provided hereincomprising: (a) dissolving the compound of formula (A-I), or apharmaceutically acceptable salt thereof, in a solvent to form asolution; (b) evaporating the solvent to form a glassy statecomposition; and (c) heating the glassy state composition to atemperature above the glass transition temperature of the glassy statecomposition and shaping the glassy state composition to form a shapedarticle. In particular embodiments, step (c) includes extruding,molding, blow molding, heat spinning, electrospinning, orelectrospraying the glassy state composition to form the shaped article.

Provided herein is a method of making an article provided hereincomprising: (a) dissolving the compound of formula (A-I), or apharmaceutically acceptable salt thereof, in a solvent to form asolution; (b) electrospraying or electrospinning the solution to form aglassy state composition; and (c) heating the glassy state compositionto a temperature above the glass transition temperature of the glassystate composition and shaping the glassy state composition to form acoating.

In certain embodiments, the method comprises producing an article thathas a glassy state.

In some embodiments, O—(R^(A))—O is a radical of a polyol formed from acyclitol (e.g., bornesitol, conduritol, inositol, ononitol, pinitol,pinpollitol, quebrachitol, quinic acid, shikimic acid, valienol, orviscumitol), a sugar alcohol (e.g., sorbitol, mannitol, xylitol,maltitol, lactitol, erythritol, isomalt), or glycerin. In particularembodiments of any of the above aspects, O—(R^(A))—O is a radical of alinear or cyclic alkane diol (e.g., 1,6-hexane diol,cyclohexyldimethanol).

In some embodiments, provided herein is a pharmaceutical compositioncomprising a compound of any compound provided herein, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.

In some embodiments, the article is free of controlled release polymer.

In particular embodiments, the article is free of a crystallizationinhibiting excipient

In certain embodiments, the article is free of a mechanical integrityenhancing excipient.

In yet further embodiments, the article is free of a binding excipient.

In some embodiments, any implant, article, or composition providedherein is suitable for administration to an individual in need thereof.

In some embodiments, provided herein is a method for treating a diseaseor disorder (e.g., or the symptoms thereof) in an individual in needthereof, the method comprising implanting any article, implant, orcomposition provided herein into the individual. In some embodiments,the disease or disorder is an acute or a chronic disease or disorder. Insome embodiments, the disease or disorder is selected from aneurodegenerative disease or disorder (e.g., Parkinson's Disease), pain,an ocular disease or disorder (e.g., glaucoma), asthma, constipation,anxiety, inflammation, psychosis, convulsion, epilepsy, infection (e.g.,microbial, bacterial, viral, fungal), cancer, diabetes, osteoporosis,arthritis, and depression.

In some embodiments, removal of the article or implant from theindividual administered the article or implant is not required (e.g.,because the implant is completely or almost completely (e.g., bio- orphysiologically) degraded or degradable (e.g., at least 80 wt. %, atleast 85 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %,at least 99 wt. %, or the like)).

In some embodiments, the article or implant is not removed (e.g.,because the implant is completely or almost completely (e.g., bio- orphysiologically) degraded or degradable (e.g., at least 80 wt. %, atleast 85 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %,at least 99 wt. %, or the like)) from an individual administered thearticle or implant.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1F show Compound 1 (dexamethasone-triethyleneglycol-dexamethasone, Dex-TEG-Dex) (FIG. 1A) formed into pellets (FIG.1B) in the glassy state. Results of testing by differential scanningcalorimetry (DSC) (FIG. 1C) and X-ray powder diffraction (XRPD) (FIG.1D) are shown, and drug release overtime was determined (FIG. 1E). FIG.1F shows representative images of the pellets incubated in drug releasemedium over time.

FIG. 2 shows a chemical structure (Indoprofen-TEG-Indoprofen, FIG. 2A)and article (FIG. 2B) exemplified herein. FIG. 2C shows a surface coatedwith the composition and the release from the coating (FIG. 2D).

FIG. 3 shows a chemical structure (Fasudil-Hep-Fasudil, FIG. 3A) andarticle (FIG. 3B) exemplified herein.

FIG. 4 shows a chemical structure (Bromfenac-TEG-Bromfenac, FIG. 4A) aswell as a surface coated with a composition (FIG. 4B) and the release ofthe composition (FIG. 4C).

FIG. 5 shows a chemical structure (Fasudil-Seb-Fasudil, FIG. 5A) andarticle (FIG. 5B) exemplified herein.

FIG. 6 shows a compound provided herein (L-Dopa-CDM-L-Dopa).

FIG. 7 shows a compound provided herein(Bromfenac-TEG-Bromfenac—formaldehyde bridge).

FIG. 8 shows a compound provided herein (Indomethacin-TEG-Indomethacin,FIG. 8A) as well as an article formed from the compound (FIG. 8B).

FIG. 9 shows a chemical structure (FIG. 9A) and article (FIG. 9B)exemplified herein (naloxone-adipate-naloxone). FIG. 9C shows the drugrelease profile for the composition (pellet) in phosphate-bufferedsaline (PBS) over 20 days. FIG. 9D represents the 20-day progression ofthe surface erosion drug release profile for the composition in PBS.

FIG. 10 shows 7-day progression of the surface erosion drug releaseprofile for a surface coated with a composition(naloxone-adipate-naloxone) provided herein in fetal bovine serum (FBS)(FIG. 10A and FIG. 10B).

FIG. 11 shows the chemical structure of a composition(naltrexone-adipate-naltrexone) provided herein.

FIG. 12 shows a chemical structure (FIG. 12A) and article (FIG. 12B)exemplified herein (Nalmefene-Adip-Nalmefene). FIG. 12C shows the drugrelease profile for the composition (pellet) in phosphate-bufferedsaline (PBS) over 14 days. FIG. 12D represents the 14-day progression ofthe surface erosion drug release profile for the composition in PBS.

FIG. 13 shows a chemical structure (FIG. 13A) and article (FIG. 13B)exemplified herein (Naloxone-Seb-Naloxone). FIG. 13C shows the drugrelease profile for the composition (pellet) in phosphate-bufferedsaline (PBS) over 14 days. FIG. 13D represents the 14-day progression ofthe surface erosion drug release profile for the composition in PBS.

FIG. 14 shows a chemical structure (FIG. 14A) and article (FIG. 14B)exemplified herein (Naloxone-CDM-Naloxone). FIG. 14C shows the drugrelease profile for the composition (pellet) in phosphate-bufferedsaline (PBS) over 14 days. FIG. 14D represents the 14-day progression ofthe surface erosion drug release profile for the composition in PBS.

FIG. 15 shows a chemical structure (FIG. 15A) and article (FIG. 15B)exemplified herein (Naltrexone-Seb-Naltrexone). FIG. 15C shows the drugrelease profile for the composition (pellet) in phosphate-bufferedsaline (PBS) over 14 days. FIG. 15D represents the 14-day progression ofthe surface erosion drug release profile for the composition in PBS.

FIG. 16 shows a chemical structure (FIG. 16A) and article (FIG. 16B)exemplified herein (Naltrexone-1,4-cyclohexyl-Naltrexone). FIG. 16Cshows the drug release profile for the composition (pellet) inphosphate-buffered saline (PBS) over 14 days. FIG. 16D represents the14-day progression of the surface erosion drug release profile for thecomposition in PBS.

FIG. 17 shows the chemical structure of a composition(Naltrexone-1,4-terephthalate-Naltrexone) that did not form a heatprocessed pellet exemplified herein.

FIG. 18 shows a chemical structure (FIG. 18A) and article (FIG. 18B)exemplified herein (Naltrexone-dodecane-Naltrexone). FIG. 18C shows thedrug release profile for the composition (pellet) in phosphate-bufferedsaline (PBS) over 14 days. FIG. 18D represents the 14-day progression ofthe surface erosion drug release profile for the composition in PBS.

FIG. 19 shows a chemical structure (FIG. 19A) and article (FIG. 19B)exemplified herein (Naltrexone-3-ethyl-3-methylglutaricacid-Naltrexone). FIG. 19C shows the drug release profile for thecomposition (pellet) in phosphate-buffered saline (PBS) over 14 days.FIG. 19D represents the 14-day progression of the surface erosion drugrelease profile for the composition in PBS.

FIG. 20 shows a chemical structure (FIG. 20A) and article (FIG. 20B)exemplified herein (Naltrexone-Hex-Naltrexone). FIG. 20C shows the drugrelease profile for the composition (pellet) in phosphate-bufferedsaline (PBS) over 14 days. FIG. 20D represents the 14-day progression ofthe surface erosion drug release profile for the composition in PBS.

FIG. 21 shows a chemical structure (FIG. 21A) and article (FIG. 21B)exemplified herein (Naltrexone-CDM-Naltrexone). FIG. 21C shows the drugrelease profile for the composition (pellet) in phosphate-bufferedsaline (PBS) over 14 days. FIG. 21D represents the 14-day progression ofthe surface erosion drug release profile for the composition in PBS.

FIG. 22 shows the chemical structure of a composition(Hydromorphone-Adip-Hydromorphone) exemplified herein.

FIG. 23 shows the chemical structure of a composition(Codeine-Adip-Codeine) exemplified herein.

DETAILED DESCRIPTION

Provided herein are prodrug dimers that can be in a crystallizable formand have unique properties that allow them to be processed as viscousfluids from a melt or solution (e.g., in order to yield shaped articleswhere most of the material is in a glassy state). The shaped articlesmay be held together by secondary (e.g., non-crystalline) interactionsand have the ability to release their prodrug/drug elements from theseshaped forms upon surface mediated degradation/dissolution. This mayprovide a controlled rate of drug release over days, weeks, months, oryears due to unique interactions between the molecules that exist in amostly amorphous state while holding the shaped form intact as thesurface erodes. This disclosure may alter the need for a carrier matrixto provide shape and form to a drug delivery depot or device, and,therefore, may mitigate the issues of phase separation of drug from thematrix, and incompatible processing conditions between the formulations'components.

The compounds and articles provided herein can be designed for thecontrolled and sustained release of a drug from the prodrug dimer usedto make the shaped article. The release rate from an article providedcan be controlled through several engineerable design parameters,including, for example, but not limited to: 1) selection of the drug; 2)selection of the functional group of the drug for conjugation (e.g., ifmultiple exist); 3) selection of the linker; 4) selection of the linkagegroup (i.e., esters, carbonates, carbonate esters, or anhydrides); 5)selection of the surface area of the shaped article; and 6) selection ofthe drug loading in the shaped article (e.g., by adding traditionalpharmaceutical excipients or mixing other drug dimers as excipients whenmaking the shaped article). In some embodiments, the controlled releaseof two or more drugs through the use of heterodimers (i.e., differentdrugs on the two ends of the linkers). Articles formed from thecompounds provided herein can yield sustained and uniform release of thedrug compounds, without exhibiting any burst release (e.g., t₁₀ can beequal to or greater than 1/10 of t₅₀) and without reliance upondegradable matrices, which can cause undesirable local side effects(such as inflammation). The high drug loading that can be present in thearticles of the disclosure are suitable for producing locally effectiveconcentrations of a drug for periods of days to weeks to months or evenyears.

Definitions

The term “annealing,” as used herein, generally refers to the process ofheating an article formed from the compound of formula (A-I) above itsglass transition temperature, Tg, (e.g., depending upon the compound,heating to 110-145° C., 130-185° C., 150-215° C., or 180-240° C.) for aperiod sufficient to reduce residual stress in the article (e.g., from 1second to 48 hours) followed by cooling.

The term “free of controlled release polymer,” as used herein, generallyrefers to the absence of an amount of a polymeric material of greaterthan 10 KDa in the articles provided herein that is sufficient to delayor slow the release of the drug dimer from the article in comparison tothe release profile observed for an otherwise identical articlecontaining none of the polymeric material, where the release profile ismeasured at 37° C. in 100% fetal bovine serum (FBS).

The term “free of a crystallization inhibiting excipient,” as usedherein, generally refers to the absence of an amount of an excipient inthe articles of the disclosure that is sufficient to reduce the amountof crystalline drug dimer in the article in comparison to the amount ofcrystalline drug dimer observed in an otherwise identical articlecontaining none of the excipient. The level of crystallinity can bemeasured using DSC or XRD. In particular embodiments, the articlesprovided herein are free of a crystallization inhibiting excipient thatis a polymeric material of greater than 10 KDa.

The term “free of a mechanical integrity enhancing excipient,” as usedherein, generally refers to the absence of an amount of an excipient inthe articles, in some embodiments herein, that is sufficient to increasethe mechanical integrity of the article in comparison to the mechanicalintegrity of an otherwise identical article containing none of theexcipient. In some embodiments, the mechanical integrity of an articlecan be tested using a 3- or 4-point mechanical bend test (ASTM C1684-18)on the formulation with or without the excipient with the article in theshape of a rod either in the dry state (prior to drug release), hydratedstate (after immersion in release medium), or after 15-30% drug releasein hydrated state. In some embodiments, (e.g., for articles with arectangular shape) the mechanical integrity can be tested using a3-point mechanical bend test (ASTM D790-17) or 4-point mechanical bendtest (ASTM D6272) on the formulation with or without excipient either inthe dry state (prior to drug release), hydrated state (after immersionin release medium) or after 15-30% drug release in hydrated state. Insome embodiments, a reduction in mechanical integrity causes thearticles to break apart sooner (e.g., increasing the total surface areaof the quantity of articles, and resulting in a more rapid releaseprofile, where the release profile is measured at 37° C. in 100% FBS).In particular embodiments, the articles of the disclosure are free of amechanical integrity enhancing excipient that is a polymeric material ofgreater than 10 KDa.

The term “free of a binding excipient,” as used herein, generally refersto the absence of an amount of an excipient in the articles of thedisclosure that is sufficient to delay or slow the release of the drugdimer from the article in comparison to the release profile observed foran otherwise identical article containing none of the binding excipient,where the release profile is measured at 37° C. in 100% FBS.

The term “anti-cancer agent,” as used herein, generally refers to a drugthat is used in the treatment of cancer. Examples of anti-cancer agentsinclude SN-38, melphalan, and podophyllotoxin.

The term “SN-38,” as used herein, generally refers to a drug having thefollowing structure:

The term “anthraquinone,” as used herein, generally refers to a drugthat belongs to the class of anthraquinone compounds. An example of ananthraquinone is diacerein.

The term “anticoagulant,” as used herein, generally refers to a drugthat prevents or reduces coagulation of blood, prolonging clotting time.An exemplary anticoagulant is warfarin.

The term “antimicrobial agent,” as used herein, generally refers to adrug that kills microorganisms or inhibits their growth. Examples ofantimicrobial agents include, e.g., cefazolin and tedizolid.

The term “antioxidant,” as used herein, generally refers to a compoundor drug that can inhibit oxidation. Exemplary antioxidants include,without limitation, ferulic acid and kaempferol.

The term “antiviral agent,” as used herein, generally refers to a drugfor the treatment of infections caused by viruses. Exemplary antiviralagents include, without limitation, trifluridine and podophyllotoxin.

The term “central nervous system agent” or “CNS agent,” as used herein,generally refers to a drug that affects the central nervous system. Anexample of a CNS agent includes L-DOPA.

The term “cylinder,” as used herein, generally refers to the shape ofthe pharmaceutical compositions of the disclosure that has parallelsides and a circular or oval cross section, or a shaped cross section(e.g., a star shaped cross section). A mean diameter of the cylinder canrange from about 0.01 to 1 mm diameter, e.g., about 0.01 to 0.2 mm,about 0.1 to 0.3 mm, about 0.1 to 0.4 mm, about 0.2 to 0.5 mm, about 0.1to 0.6 mm, about 0.1 to 0.7 mm, about 0.1 to 0.8 mm, or about 0.1 to 0.9mm. A mean length of the cylinder can range from about 0.05 to 20 mm,e.g., about 0.05 to 1 mm, about 0.5 to 2 mm, about 0.5 to 4 mm, about0.5 to 6 mm, about 0.5 to 8 mm, about 0.5 to 10 mm, about 0.5 to 12 mm,about 0.5 to 14 mm, about 0.5 to 16 mm, or about 0.5 to 18 mm. In someembodiments, the mean diameter of the cylinder is in the range of about0.01 to 1 mm and the mean length of the cylinder is about 0.1 mm to 4.0mm. In some embodiments, the mean length of the cylinder is about 0.5 to10 mm, or about 1 to 10 mm.

The term “fiber,” as used herein, generally refers to the shape of thepharmaceutical compositions of the disclosure that is elongated orthreadlike. A mean diameter of the fiber can range from about 0.01 to 1mm, e.g., 0.05 to 0.3 mm, 0.1 to 0.3 mm, 0.15 to 0.3 mm, 0.2 to 0.3 mm,0.25 to 0.3 mm, 0.01 to 0.1 mm, 0.01 to 0.2 mm, 0.01 to 0.3 mm, 0.01 to0.4 mm, 0.01 to 0.5 mm, 0.01 to 0.6 mm, 0.01 to 0.7 mm, 0.01 to 0.8 mm,or 0.01 to 0.9 mm. A mean length of the fiber can range from about 20 to20,000 mm, e.g., about 20 to 1000 mm, about 20 to 2,000 mm, about 100 to2,000 mm, about 100 to 5,000 mm, about 1,000 to 8,000 mm, about 2,000 to8,000 mm, about 2,000 to 10,000 mm, about 2,000 to 12,000 mm, about2,000 to 15,000 mm, or about 5,000 to 18,000 mm.

The term “fiber mesh,” as used herein, generally refers to a web or anet in having many attached or woven fibers. The fiber mesh can havealigned and unaligned morphologies.

The term “glassy state,” as used herein, generally refers to anamorphous solid including greater than 70%, 80%, 90%, 95%, 98%, or 99%(w/w) of one or more drug dimers of the invention and exhibiting a glasstransition temperature above 38° C. In the glassy state, as measured byDSC or XRD, the level of crystallinity is low, ranging from 0-15%, e.g.,0-1%, 0-3%, 0-5%, 0-7%, 0-9%, 0-10%, or 0-13%. Glass formulations of theinvention can be formed using heat processing or solvent processing oneor more drug dimers.

The term “microparticle,” as used herein, generally refers to the shapeof the pharmaceutical compositions of the disclosure, which can beregularly or irregularly shaped. A mean diameter of the microparticlecan range from about 1 to 1000 μm, e.g., about 10 to 1000 μm, about 100to 1000 μm, about 200 to 1000 μm, about 500 to 1000 μm, about 700 to1000 μm, or about 900 to 1000 μm. As used herein, a “microbead” refersto a microparticle that is spherical.

The term “nanoparticle,” as used herein, generally refers to the shapeof the pharmaceutical compositions of the disclosure, which can beregularly or irregularly shaped. A mean diameter of the nanoparticle canrange from about 0.01 to 1 μm, e.g., about 0.05 to 1 μm, about 0.1 to 1μm, about 0.2 to 1 μm, about 0.3 to 1 μm, about 0.4 to 1 μm, about 0.5to 1 μm, about 0.6 to 1 μm, about 0.7 to 1 μm, about 0.8 to 1 μm, orabout 0.9 to 1 μm. As used herein, a “nanobead” refers to a nanoparticlethat is spherical.

The term “nonsteroidal anti-inflammatory drug” or “NSAID,” as usedherein, generally refers to a drug that reduces pain, decreases fever,prevents blood clots and, in higher doses, decreases inflammation.Exemplary nonsteroidal anti-inflammatory drugs include, withoutlimitation, pranoprofen, bromfenac, and indoprofen.

The term “non-woven fabric,” as used herein, generally refers to a webstructure bonded together by entangling fibers.

The term “analgesic,” as used herein, generally refers to a powerfulpain-reducing medication. Exemplary analgesics are oxycodone andmorphine.

The term “pellet,” as used herein, generally refers to the shape of thepharmaceutical compositions of the disclosure that is rounded,spherical, or cylindrical, or a combination thereof. A mean diameter ofthe pellet can range from about 0.2 to 5 mm, e.g., from about 0.2 to 1mm, from about 0.2 to 2 mm, from about 0.3 to 3 mm, from about 1.5 to 5mm, from about 2 to 5 mm, from about 2.5 to 5 mm, from about 3 to 5 mm,from about 3.5 to 5 mm, from about 4 to 5 mm, or from about 4.5 to 5 mm.

The term “pharmaceutically acceptable salt” as used herein, generallyrepresents those salts which are, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andanimals without undue toxicity, irritation, allergic response and thelike and are commensurate with a reasonable benefit/risk ratio.Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in J. Pharm. Sci. 66:1-19, 1977. The salts can be prepared insitu during the final isolation and purification of the compounds of thedisclosure or separately by reacting the free base group with a suitableorganic acid. Representative acid addition salts include acetate,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphersulfonate, carbonate,chloride, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptonate, glycerophosphate,hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride,hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate,lauryl sulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like, as well asnontoxic ammonium, quaternary ammonium, and amine cations, including,but not limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like.

The term “rho kinase inhibitor” or “ROCK inhibitor” generally refers toa drug that targets rho kinase. Exemplary ROCK inhibitors include,without limitation, ripasudil and fasudil.

The term “surface erosion,” as used herein, generally refers to aprocess of a gradual disintegration of the pharmaceutical compositionsof the disclosure and release of a free drug from the drug dimer.Surface erosion can be tailored to achieve desired drug release rates.Surface erosion can depend on the drug composition of the drug dimer,and can be modulated by the cleavage of drug-linker bond throughhydrolysis and/or enzymatic degradation. The rate of surface erosion andrelease of a given drug from a drug dimer may also depend on thequantity of the loaded drug dimer as a percent of the final drug dimerformulation, article size (e.g. dimensions), solubility of drug dimer(e.g., through selection of appropriate drug and/or linker), and/orsurface area of the article. For example, surface erosion mechanism ofdrug release allows drug delivery articles to be tailored with specificphysical features (dimensions, diameters, surface areas, total mass,etc.) to achieve desired drug release rates, and drug release may bedesigned to be initiated within minutes or hours, and may continue tooccur over days, weeks, months, or years.

As used herein, “t₅₀” generally refers to the time at which 50% of thereleasable drug has been released from an article of the invention. Timet₁₀ is, correspondingly, the time at which 10% of the releasable drughas been released from an article of the invention. When the releasecurve is perfectly linear, t₁₀=⅕ of t₅₀. When there is an initial burstof released drug, t₁₀ is much less than ⅕ of t₅₀. In the compositionsand methods of the disclosure, t₁₀ can be equal to or greater than 1/10of t₅₀. Drug release from an article or compound of the disclosure canbe measured at 37° C. in 100% bovine serum, or at 37° C. in phosphatebuffered saline (PBS), as described in Example 1.

The term “woven fabric,” as used herein, generally refers topharmaceutical compositions that resemble materials that are formed byweaving of fibers.

Chemical Definitions

By “acyl” is meant a chemical moiety with the formula —C(O)R′, where R′is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₂₀ alkene,heteroalkyl, C₂₋₂₀ alkyne, C₅₋₁₀ aryl, and cyclic system. Examples ofacyl groups include, without limitation, acetyl, propanoyl, butanoyl,pentanoyl, and tetrahydrofuran-2-oyl.

By “aliphatic” is meant a non-aromatic chemical moiety of hydrocarbons.Aliphatics may be cyclic, straight, or branched chains, and may besaturated or unsaturated, and may have single, double, or triple bonds.

By “alkoxy” is meant a chemical substituent of the formula —OR, whereinR is an alkyl group. By “aryloxy” is meant a chemical substituent of theformula —OR, wherein R is a C₅₋₁₀ aryl group.

As used herein, the terms “alkylene,” “alkenylene,” “alkynylene,” andthe prefix “alk” refer to divalent groups having a specified size,typically C₁₋₁₀ or C₁₋₂₀ for the saturated groups (e.g., alkylene oralk) and C₂₋₂₀ or C₂₋₂₀ for the unsaturated groups (e.g., alkenylene oralkynylene). They include straight-chain, branched-chain, and cyclicforms as well as combinations of these, containing only C and H whenunsubstituted. Because they are divalent, they can link together twoparts of a molecule. Examples are methylene, ethylene, propylene,cyclopropan-1,1-diyl, ethylidene, 2-butene-1,4-diyl, and the like. Thesegroups can be substituted by the groups typically suitable assubstituents for alkyl, alkenyl and alkynyl groups as set forth herein.Thus C═O is a C1 alkylene that is substituted by ═O, for example.

By “alkylthio” is meant a chemical substituent of the formula —SR,wherein R is an alkyl group.

By “arylthio” is meant a chemical substituent of the formula —SR,wherein R is a C₅₋₁₀ aryl group.

By “C₁₋₂₀ alkyl” is meant a branched or unbranched saturated hydrocarbongroup, having 1 to 20 carbon atoms, inclusive. An alkyl may optionallyinclude monocyclic, bicyclic, or tricyclic rings, in which each ringdesirably has three to six members. The alkyl group may be substitutedor unsubstituted. Exemplary substituents include alkoxy, aryloxy,sulfhydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl,perfluoralkyl, amino, aminoalkyl, disubstituted amino, quaternary amino,hydroxyalkyl, carboxyalkyl, and carboxyl groups.

By “C₂₋₂₀ alkene” is meant a branched or unbranched hydrocarbon groupcontaining one or more double bonds, desirably having from 2 to 10carbon atoms. A C₂₋₂₀ alkene may optionally include monocyclic,bicyclic, or tricyclic rings, in which each ring desirably has five orsix members. The C₂₋₂₀ alkene group may be substituted or unsubstituted.Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino,aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,carboxyalkyl, and carboxyl groups.

By “C₂₋₂₀ alkyne” is meant a branched or unbranched hydrocarbon groupcontaining one or more triple bonds, desirably having from 2 to 10carbon atoms. A C₂₋₂₀ alkyne may optionally include monocyclic,bicyclic, or tricyclic rings, in which each ring desirably has five orsix members. The C₂₋₂₀ alkyne group may be substituted or unsubstituted.Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino,aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,carboxyalkyl, and carboxyl groups.

By “carbonate ester” is meant a linkage group having the formula—C(O)O—C(O)—O—.

By “carboxyalkyl” is meant a chemical moiety with the formula —(R)—COOH,wherein R is an alkyl group.

By “cyclic acetal” is meant a ring structure including two oxygen atomsseparated by a carbon atom which is optionally substituted (e.g.,1,3-dioxolane). Exemplary substituents include, without limitation,alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio, arylthio,halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl,monosubstituted amino, disubstituted amino, quaternary amino,phosphodiester, phosphoramidate, phosphate, phosphonate, phosphonateester, sulfonate, sulfate, sulfhydryl, phenol, amidine, guanidine, andimidazole groups.

The term “cyclic system” refers to a compound that contains one or morecovalently closed ring structures, in which the atoms forming thebackbone of the ring are composed of any combination of the following:carbon, oxygen, nitrogen, sulfur, and phosphorous. The cyclic system maybe substituted or unsubstituted. Exemplary substituents include, withoutlimitation, alkyl, hydroxyl, alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino,aminoalkyl, monosubstituted amino, disubstituted amino, and quaternaryamino groups.

By “fluoroalkyl” is meant an alkyl group that is substituted with afluorine.

By “heteroalkyl” is meant a branched or unbranched alkyl group in whichone or more methylenes (—CH₂—) are replaced by nitrogen, oxygen, sulfur,carbonyl, thiocarbonyl, phosphoryl, or sulfonyl moieties. Some examplesinclude tertiary amines, ethers, thioethers, amides, thioamides,carbamates, thiocarbamates, phosphoramidates, sulfonamides, anddisulfides. A heteroalkyl may optionally include monocyclic, bicyclic,or tricyclic rings, in which each ring desirably has three to sixmembers. The heteroalkyl group may be substituted or unsubstituted.Exemplary substituents include alkoxy, aryloxy, sulfhydryl, alkylthio,arylthio, halogen, hydroxyl, fluoroalkyl, perfluoralkyl, amino,aminoalkyl, disubstituted amino, quaternary amino, hydroxyalkyl,carboxyalkyl, and carboxyl groups.

By “hydroxyalkyl” is meant a chemical moiety with the formula —(R)—OH,wherein R is an alkyl group.

In general, alkyl groups are each independently substituted orunsubstituted. Each recitation of “alkyl” provided herein, unlessotherwise stated, includes a specific and explicit recitation of anunsaturated “alkyl” group. Similarly, unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), aryl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aralkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), heteroaryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl).

“Carbocyclyl” or “cycloalkyl” refers to a stable non-aromatic monocyclicor polycyclic hydrocarbon radical consisting solely of carbon andhydrogen atoms, which includes fused or bridged ring systems, havingfrom three to fifteen carbon atoms. In certain embodiments, acarbocyclyl comprises three to ten carbon atoms. In other embodiments, acarbocyclyl comprises five to seven carbon atoms. The carbocyclyl isattached to the rest of the molecule by a single bond. Carbocyclyl orcycloalkyl is saturated (i.e., containing single C—C bonds only) orunsaturated (i.e., containing one or more double bonds or triple bonds).Examples of saturated cycloalkyls include, e.g., cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Anunsaturated carbocyclyl is also referred to as “cycloalkenyl.” Examplesof monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicalsinclude, for example, adamantyl, norbornyl (i.e.,bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “carbocyclyl” ismeant to include carbocyclyl radicals that are optionally substituted byone or more substituents independently selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), cycloalkylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl), each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

In general, optionally substituted groups are each independentlysubstituted or unsubstituted. Each recitation of an optionallysubstituted group provided herein, unless otherwise stated, includes anindependent and explicit recitation of both an unsubstituted group and asubstituted group (e.g., substituted in certain embodiments, andunsubstituted in certain other embodiments). Unless otherwise stated,substituted groups may be substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—OC(O)—N(R^(a))₂, —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where t is1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl(optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), carbocyclylalkyl (optionally substituted with halogen,hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl),heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), heterocyclylalkyl (optionally substituted withhalogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionallysubstituted with halogen, hydroxy, methoxy, or trifluoromethyl), orheteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy,or trifluoromethyl).

Provided is a compound of formula (A-I) and articles formed from acompound of formula (A-I):

D1-L-D2  (A-I),

or a pharmaceutically acceptable salt thereof, wherein each of D1 and D2is, independently, a radical formed from a drug; and L is a linkercovalently linking D1 to D2. Each of D1 and D2 can be, independently,selected from a nonsteroidal anti-inflammatory drug (NSAID), an (e.g.,opioid) analgesic, a CNS agent, a ROCK inhibitor, an anthraquinone, ananti-cancer agent, an antiviral agent, an antioxidant, a muscarinicantagonist, an antimicrobial agent, or an anticoagulant. In someembodiments, the article or compound provided herein does not comprisean opioid radical. In some embodiments, the article or compound providedherein does not release an opioid conjugate or an opioid radical in itsfree form. L can be covalently linked to D1 and to D2 via one or moreester, carbonate, carbonate ester, anhydride, amide, or carbamatelinkages. Ester, carbonate, carbonate ester, or anhydride linkagesformed from a functional group on D1 and D2 can be selected from, e.g.,hydroxyl or carboxyl. For example, L can include the radical—C(O)—(R^(A))—C(O)—, —C(O)—OC(O)—(R^(A))—C(O)O—C(O)—, or —O—(R^(A))—O—,where R^(A) is a radical of a polyol and includes at least one freehydroxyl group or R^(A) is selected from C₁₋₂₀ alkylene, a linear orbranched heteroalkylene of 1 to 20 atoms, a linear or branched C₂-20alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, acyclic system of 3 to 10 atoms, —(CH₂CH₂O)_(q)CH₂CH₂—,—(CH₂CH₂CH₂CH₂O)_(r)CH₂CH₂CH₂CH₂—, or —(CH₂CH(CH₃)O)_(s)CH₂CH(CH₃)—, andq, r, and s are integers from 1 to 10 (e.g., 1 to 10, 1 to 5, or 5 to10). The articles of the disclosure can be machined, molded,emulsion-processed, electrospun, electrosprayed, blow molded, orextruded to form a fiber, fiber mesh, woven fabric, non-woven fabric,film, surface coating, pellet, cylinder, microparticle, nanoparticle, oranother shaped article.

Drugs Dimerized Via a Hydroxy Moiety

In some embodiments, the compound has a structure of formula (A-II):

D1-O-L-O-D2  (A-II),

or a pharmaceutically acceptable salt thereof, wherein each of D1-O andD2-O is, independently, a radical formed from a drug bearing a hydroxylgroup; L is —C(O)—(R^(A))—C(O)— or —C(O)—O—(R^(A))—O—C(O)—; R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. Each of D1-O and D2-O        can, independently, be formed, for example, from        podophyllotoxin, SN-38, trifluridine, kaempferol, tedizolid,        warfarin, resveratrol, epinephrine, forskolin, doxorubicin,        erythromycin, etoposide, sirolimus, phenytoin, DL-atenolol,        thalidomide, acetazolamide, chloroxine, stavudine,        sulfacetamide, meloxicam, salbutamol, haloperidol, zileuton,        piroxicam, primidone, (−)-chloramphenicol, cladribine,        chlortalidone, losartan, L-methyldopa, mitoxantrone, carbidopa,        dicoumarol, pindolol, (E)-entacapone, hydroxyzine, propranolol,        amoxicillin, cefdinir, labetalol, pemetrexed, digoxin, abacavir,        metirosine, cefradine, nelarabine, lorazepam, isoprenaline,        oxazepam, daunorubicin, fenamisal, misoprostol, (−)-S-timolol,        miglustat, tetracycline, (+)-tramadol, digitoxin, spectinomycin,        masoprocol, levobunolol, chlortetracycline, novobiocin,        ergotamine, rifaximin, methysergide, cefmenoxime, cefaloglycin,        or nitroxoline, or described by any one of formulas (I-e)-(I-v),        and (I-y)-(I-ax):

Drugs Dimerized Via a Carboxy Moiety

In some embodiments, the compound has a structure of formula (A-III):

D1-C(O)-L-C(O)-D2  (A-III),

or a pharmaceutically acceptable salt thereof, wherein each of D1-C(O)and D2-C(O) is, independently, a radical formed from a drug bearing acarboxyl group; L is —O—(R^(A))—O—, —O—C(O)—O—(R^(A))—O—C(O)—O—, or—NH—(R^(A))—NH—; R^(A) is selected from C₁₋₂₀ alkylene, a linear orbranched heteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, acyclic system of 3 to 10 atoms, or O—(R^(A))—O is a radical of a polyoland includes at least one free hydroxyl group or O—(R^(A))—O is selectedfrom:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. Each of D1-C(O) and        D2-C(O) can, independently, be formed, for example, from        pranoprofen, bromfenac, indoprofen, L-DOPA, diacerein,        melphalan, ferulic acid, cefazolin, flutathione, methotrexate,        indomethacin, furosemide, naproxen, nalidixic acid, baclofen,        bumetanide, amlexanox, L-methyldopa, lisinopril, carbidopa,        D-(−)-ampicillin, cefalotin, cetirizine, amoxicillin, cefdinir,        metirosine, nedocromil, cefixime, piperacillin, ceforanide,        cefuroxime, gabapentin, benazeprilat, or ketorolac. In the drug        dimers of formula (A-III), D1-C(O)— and D2-C(O)— can further be        described, for example, by formulas (I-y) to (I-af) below.

Drugs Dimerized Via an Amino Moiety

In some embodiments the compound has a structure of formula (A-IV):

D1-NH—C(O)-L-C(O)—NH-D2  (A-IV),

or a pharmaceutically acceptable salt thereof, wherein each of D1-NH andD2-NH is, independently, a radical formed from a drug bearing a primaryamino functional group; L is —O—(R^(A))—O— or —(R^(A))—; R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10.

In some embodiments, the compound has a structure of formula (A-V):

or a pharmaceutically acceptable salt thereof, wherein each of

is, independently, a radical formed from a drug bearing a secondaryamino functional group; L is —O—(R^(A))—O— or —(R^(A))—; R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10. In these embodiments, the        moiety O—(R^(A))—O can be a radical of a polyol formed from a        cyclitol, a sugar alcohol, a linear or cyclic alkane diol, or        glycerin. In particular embodiments, O—(R^(A))—O is a radical        formed from an alkane diol, diethylene glycol, triethylene        glycol, tetraethylene glycol, or pentaethylene glycol.

In some embodiments, the compound has a structure of formula (A-VI):

D1-N═C(R¹)-L-C(R¹)═NH-D2  (A-VI),

or a pharmaceutically acceptable salt thereof, wherein each of D1-N andD2-N is, independently, a radical formed from a drug bearing a primaryamino functional group; R¹ is a H or C₁₋₄ alkyl; L is —(R^(A))—; andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms.

In some embodiments, the compound has a structure of formula (A-VII):

D1-NH-L-NH-D2  (A-VII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-N andD2-N is, independently, a radical formed from a drug bearing a primaryamino functional group; and L is —CH₂—O—C(O)—O—(R^(A))—O—C(O)—O—CH₂—,—CH(CH₃)—O—C(O)—O—(R^(A))—O—C(O)—O—CH(CH₃)—; and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10.

Each of the drugs bearing a primary or secondary amino functional groupcan, independently, be formed, for example, from epinephrine,trifluridine, mitomycin C, fluorouracil, glutathione, doxorubicin,methotrexate, nifedipine, prazosin, bromidinidine, trimethoprim,theophylline, carbamazepine, sulfamethoxazole, omeprazole, furosemide,tiabendazole, hydrochlorothiazide, DL-atenolol, dapsone, pyrimethamine,albendazole, sulfadiazine, acetazolamide, lamotrigine, sulfapyridine,lansoprazole, zonisamide, azathioprine, valdecoxib, imiquimod, baclofen,sulfacetamide, bumetanide, salbutamol, oxcarbazepine, torasemide,sulfafurazole, zileuton, tadalafil, topamax, mafenide, famotidine,indapamide, cladribine, chlortalidone, adefovir dipivoxil, amlexanox,felbamate, isradipine, amoxapine, clozapine, brimonidine,sulfamethoxydiazine, metolazone, (E)-nitrofurazone, ILosartan,L-methyldopa, lisinopril, hydroflumethiazide, dofetilide, minoxidil,nepafenac, mitoxantrone, carbidopa, sulfamethizole, pindolol,primaquine, D-(−)-ampicillin, diclofenamide, melphalan, sulfaphenazole,bupropion, (E)-nizatidine, propranolol, sumatriptan, amoxicillin,cefdinir, labetalol, valaciclovir, pemetrexed, abacavir, metirosine,amiloride, cefradine, nelarabine, (E)-dacarbazine, bendroflumethiazide,methyclothiazide, isoprenaline, ethoxzolamide, daunorubicin, fenamisal,cefixime, benzthiazide, dorzolamide, (−)-S-timolol, tocainide,neptazane, tetracycline, guanfacine, trimetrexate, spectinomycin,methylphenidate, levobunolol, guanethidine, cyclothiazide, guanabenz,chlortetracycline, novobiocin, polythiazide, ergotamine,acetylsulfafurazole, ceforanide, quinethazone, sulfacytine, cefmenoxime,cefaloglycin, cefuroxime, gabapentin, benazeprilat, tamsulosin,ripasudil, or fasudil. In the drug dimers of formulas (A-IV)-(A-VII),the drug radical can further be described, for example, by formula(I-ag) to (I-ax) below.

Drugs Dimerized Via an Enolizable Ketone Moiety

In some embodiments, the compound has a structure of formula (A-VIII):

D1-E-L-E-D2  (A-VIII),

or a pharmaceutically acceptable salt thereof, wherein each of D1-E andD2-E is, independently, a radical formed from a drug bearing anenolizable ketone functional group (i.e., a ketone adjacent a C—H groupthat together permit an enol tautomerization); L is —C(O)—(R^(A))—C(O)—or —C(O)—O—(R^(A))—O—C(O)—; R^(A) is selected from C₁₋₂₀ alkylene, alinear or branched heteroalkylene of 1 to 20 atoms, a linear or branchedC₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀arylene, a cyclic system of 3 to 10 atoms, or O—(R^(A))—O is a radicalof a polyol and comprises at least one free hydroxyl group or isselected from:

-   -   —O(CH₂CH₂O)_(n)CH₂CH₂O—,    -   —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, or    -   —O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and        n, m, and p are integers from 1 to 10.

Drug dimers useful in the methods and compositions of the disclosureinclude homodimers and heterodimers. Drugs, including nonsteroidalanti-inflammatory drugs (NSAIDs), CNS agents, ROCK inhibitors,anthraquinones, anti-cancer agents, antiviral agents, antioxidants,muscarinic antagonists, antimicrobial agents, and anticoagulants, can beused in drug dimers. Examples of NSAIDs include pranoprofen, bromfenac,and indoprofen. An exemplary CNS agent is L-DOPA. Exemplary ROCKinhibitors include ripasudil and fasudil. An exemplary anthraquinone isdiacerein. Exemplary anti-cancer agents are podophyllotoxin, SN-38, andmelphalan. Exemplary antioxidants are ferulic acid and kaempferol.Exemplary antimicrobial agents include cefazolin and tedizolid.Exemplary antiviral agents include trifluridine and podophyllotoxin. Anexemplary anticoagulant is warfarin.

The drug dimers useful in making the articles of the disclosure can haveany of formulas (II)-(IV), (IX)-(XXXIV), and (XLII)-(XLIV), describedherein.

Drug Homodimers

The disclosure features homodimers of the formula (A-I):

D1-L-D2  (A-I)

or a pharmaceutically acceptable salt thereof, wherein D1, D2, and L areas described above. The homodimer can be further described by one offormulas (II)-(IV), (IX)-(XXXIV), and (XLII)-(XLIV), below.

In some embodiments, the drug is a nonsteroidal anti-inflammatory drug(NSAID) and the drug dimer is further described by the formula (II):

wherein L is —C(O)—(R^(A))—C(O)—, —(R^(A))—, C(O)—O—(R^(A))—O—C(O)— andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (II) can be formed from the NSAIDpranoprofen.

In some embodiments, the drug is an NSAID and the drug dimer is furtherdescribed by the formula (III):

wherein L is —C(O)—(R^(A))—C(O)—, —(R^(A)), C(O)—O—(R^(A))—O—C(O)— andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (III) can be formed from the NSAIDbromfenac.

In some embodiments, the drug is an NSAID and the drug dimer is furtherdescribed by the formula (IV):

wherein L is —C(O)—(R^(A))—C(O)—, —(R^(A))—, C(O)—O—(R^(A))—O—C(O)— andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (IV) can be formed from the NSAIDindoprofen.

In some embodiments, the drug is a CNS agent and the drug dimer isfurther described by the formula (IX):

wherein L is —C(O)—(R^(A))—C(O)—, —(R^(A))—, C(O)—O—(R^(A))—O—C(O)— andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (IX) can be formed from the CNS agentL-DOPA.

In some embodiments, the drug is a CNS agent and the drug dimer isfurther described by the formula (X):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (X) can be formed from the CNS agentL-DOPA.

In some embodiments, the drug is a CNS agent and the drug dimer isfurther described by the formula (XI):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XI) can be formed from the CNS agentL-DOPA.

In some embodiments, the drug is a ROCK inhibitor and the drug dimer isfurther described by formula (XII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or —O—(R^(A))—O— and R^(A) is selected from C₁₋₂₀ alkylene, alinear or branched heteroalkylene of 1 to 20 atoms, a linear or branchedC₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀arylene, a cyclic system of 3 to 10 atoms, or O—(R^(A))—O is a radicalof a polyol and includes at least one free hydroxyl group or O—(R^(A))—Ois selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XII) can be formed from the ROCKinhibitor ripasudil.

In some embodiments, the drug is a ROCK inhibitor and the drug dimer isfurther described by the formula (XIII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or —O—(R^(A))—O— and R^(A) is selected from C₁₋₂₀ alkylene, alinear or branched heteroalkylene of 1 to 20 atoms, a linear or branchedC₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀arylene, a cyclic system of 3 to 10 atoms, or O—(R^(A))—O is a radicalof a polyol and includes at least one free hydroxyl group or O—(R^(A))—Ois selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XIII) can be formed from the ROCKinhibitor fasudil.

In some embodiments, the drug is an anthraquinone and the drug dimer isfurther described by the formula (XIV):

wherein L is —C(O)—(R^(A))—C(O)—, —(R^(A)), C(O)—O—(R^(A))—O—C(O)— andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XIV) can be formed from the anthraquinonediacerein.

In some embodiments, the drug is an anti-cancer or antiviral agent andthe drug dimer is further described by the formula (XV):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XV) can be formed from the anti-cancer orantiviral agent is podophyllotoxin.

In some embodiments, the drug is an anti-cancer agent and the drug dimeris further described by the formula (XVI):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XVI) can be formed from the anti-canceragent is SN-38.

In some embodiments, the drug is an anti-cancer agent and the drug dimeris further described by the formula (XVII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XVII) can be formed from the anti-canceragent is SN-38.

In some embodiments, the drug is an anti-cancer agent and the drug dimeris further described by the formula (XVIII):

wherein L is —C(O)—(R^(A))—C(O)—, —(R^(A))—, C(O)—O—(R^(A))—O—C(O)— andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XVIII) can be formed from the anti-canceragent is melphalan.

In some embodiments, the drug is an antioxidant and the drug dimer isfurther described by the formula (XIX):

wherein L is —C(O)—(R^(A))—C(O)—, —(R^(A)), C(O)—O—(R^(A))—O—C(O)— andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XIX) can be formed from the antioxidantferulic acid.

In some embodiments, the drug is an antioxidant and the drug dimer isfurther described by the formula (XX):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XX) can be formed from the antioxidantferulic acid.

In some embodiments, the drug is an antioxidant and the drug dimer isfurther described by the formula (XXI):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXI) can be formed from the antioxidantkaempferol.

In some embodiments, the drug is an antioxidant and the drug dimer isfurther described by the formula (XXII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXII) can be formed from the antioxidantkaempferol.

In some embodiments, the drug is an antioxidant and the drug dimer isfurther described by the formula (XXIII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXIII) can be formed from the antioxidantkaempferol.

In some embodiments, the drug is an antioxidant and the drug dimer isfurther described by the formula (XXIV):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXIV) can be formed from the antioxidantkaempferol.

In some embodiments, the drug is an antimicrobial agent and the drugdimer is further described by the formula (XXVI):

wherein L is —C(O)—(R^(A))—C(O)—, —(R^(A)), C(O)—O—(R^(A))—O—C(O)— andR^(A) is selected from C₁₋₂₀ alkylene, a linear or branchedheteroalkylene of 1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene,a linear or branched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic systemof 3 to 10 atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected fromC₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, alinear or branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXVI) can be formed from theantimicrobial agent cefazolin.

In some embodiments, the drug is an antimicrobial agent and the drugdimer is further described by the formula (XXVII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXVII) can be formed from theantimicrobial agent tedizolid.

In some embodiments, the drug is an antiviral agent and the drug dimeris further described by the formula (XXVIII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXVIII) can be formed from the antiviralagent trifluridine.

In some embodiments, the drug is an antiviral agent and the drug dimeris further described by the formula (XXIX):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXIX) can be formed from the antiviralagent trifluridine.

In some embodiments, the drug is an anticoagulant and the drug dimer isfurther described by the formula (XXX):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXX) can be formed from the anticoagulantwarfarin.

In some embodiments, the drug is an NSAID and the drug dimer is furtherdescribed by the formula (XXXI):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXI) can be formed from the NSAIDbromfenac.

In some embodiments, the drug is a CNS agent and the drug dimer isfurther described by the formula (XXXII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is a radical of a polyol and includes at least onefree hydroxyl group or O—(R^(A))—O is selected from—O(CH₂CH₂O)_(n)CH₂CH₂O—, —O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXII) can be formed from the CNS agentL-DOPA.

In some embodiments, the drug is an anti-cancer agent and the drug dimeris further described by the formula (XXXIII):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXIII) can be formed from theanti-cancer agent is melphalan.

In some embodiments, the drug is a neural-protective and anti-oxidantand the drug dimer is further described by the formula (XXXIV):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected from C₁₋₂₀alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linearor branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀ alkynylene, aC₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, or O—(R^(A))—O is aradical of a polyol and includes at least one free hydroxyl group orO—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXIV) can be formed from theneural-protective and anti-oxidant resveratrol.

In some embodiments, the drug is a neural-protective and anti-oxidantand the drug dimer is further described by the formula (XXXV):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected from C₁₋₂₀alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linearor branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀ alkynylene, aC₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, or O—(R^(A))—O is aradical of a polyol and includes at least one free hydroxyl group orO—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXV) can be formed from theneural-protective and anti-oxidant resveratrol.

In some embodiments, the drug is an antineoplastic and the drug dimer isfurther described by the formula (XXXVI):

wherein L is —C(O)—(R^(A))—C(O)— or —C(O)—O—(R^(A))—O—C(O)—; R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms; orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXVI) can be formed from theantineoplastic fluorouracil.

In some embodiments, the drug is an antineoplastic and the drug dimer isfurther described by the formula (XXXVII):

wherein L is —C(O)—(R^(A))—C(O)— or —C(O)—O—(R^(A))—O—C(O)— and R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms; orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXVII) can be formed from theantineoplastic fluorouracil.

In some embodiments, the drug is an alpha-adrenergic agonist,antiglaucoma drug, bronchodilator, or mydriatic and the drug dimer isfurther described by the formula (XXXVIII):

wherein L is —C(O)—(R^(A))—C(O)— or —C(O)—O—(R^(A))—O—C(O)— and R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms; orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXVIII) can be formed from thealpha-adrenergic agonist, antiglaucoma drug, bronchodilator, andmydriatic epinephrine.

In some embodiments, the drug is an alpha-adrenergic agonist,antiglaucoma drug, bronchodilator, or mydriatic and the drug dimer isfurther described by the formula (XXXIX):

wherein L is —C(O)—(R^(A))—C(O)—, or —C(O)—O—(R^(A))—O—C(O)— and R^(A)is selected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of1 to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear orbranched C₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10atoms; or —O-L-O— is —O—(R^(A))—O— and R^(A) is selected from C₁₋₂₀alkylene, a linear or branched heteroalkylene of 1 to 20 atoms, a linearor branched C₂₋₂₀ alkenylene, a linear or branched C₂₋₂₀ alkynylene, aC₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms, or O—(R^(A))—O is aradical of a polyol and includes at least one free hydroxyl group orO—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XXXIX) can be formed from thealpha-adrenergic agonist, antiglaucoma drug, bronchodilator, andmydriatic epinephrine.

In some embodiments, the drug is an antibiotic or antineoplastic and thedrug dimer is further described by the formula (XLII):

wherein L is —C(O)—(R^(A))—C(O)— or —C(O)—O—(R^(A))—O—C(O)— and R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms; orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XLII) can be formed from the antibioticand antineoplastic mitomycin C.

In some embodiments, the drug is an antibiotic or antineoplastic and thedrug dimer is further described by the formula (XLIII):

wherein L is —C(O)—(R^(A))—C(O)— or —C(O)—O—(R^(A))—O—C(O)— and R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms; orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XLIII) can be formed from the antibioticand antineoplastic mitomycin C.

In some embodiments, the drug is an antibiotic or antineoplastic and thedrug dimer is further described by the formula (XLIV):

wherein L is —C(O)—(R^(A))—C(O)— or —C(O)—O—(R^(A))—O—C(O)— and R^(A) isselected from C₁₋₂₀ alkylene, a linear or branched heteroalkylene of 1to 20 atoms, a linear or branched C₂₋₂₀ alkenylene, a linear or branchedC₂₋₂₀ alkynylene, a C₅₋₁₀ arylene, a cyclic system of 3 to 10 atoms; orO—(R^(A))—O is a radical of a polyol and includes at least one freehydroxyl group or O—(R^(A))—O is selected from —O(CH₂CH₂O)_(n)CH₂CH₂O—,—O(CH₂CH₂CH₂CH₂O)_(m)CH₂CH₂CH₂CH₂O—, and—O(CH₂CH(CH₃)O)_(p)CH₂CH(CH₃)O—; and n, m, and p are integers from 1 to10. The drug dimer of formula (XLIV) can be formed from the antibioticand antineoplastic mitomycin C.

In some embodiments, the compound, or pharmaceutically acceptable saltthereof, provided in Table 1 comprises both a first radical and a secondradical, which when combined in a dimer are processable (e.g., whereinthe radicals may or may not be processable themselves, when in theirfree form) (e.g., FIG. 2-FIG. 8). In some embodiments, the compound, orpharmaceutically acceptable salt thereof, provided in Table 1 comprisesa first radical and a second radical that are the same. In someembodiments, both the first radical and the second radical of theconjugate, or pharmaceutically acceptable salt thereof, provided inTable 1 is attached to the linker at a hydroxyl, a carboxylate, or anamine of each the first radical and the second radical.

TABLE 1 Example Structure Name 1

(ethane-1,2- diylbis(oxy))bis(ethane- 2,1-diyl) bis(2-(4-(1-oxoisoindolin-2- yl)phenyl)propanoate) 2

1,10-bis(4-(isoquinolin- 5-ylsulfonyl)-1,4- diazepan-1-yl)decane-1,10-dione 3

(ethane-1,2- diylbis(oxy))bis(ethane- 2,1-diyl) bis(2-(2-amino- 3-(4-bromobenzoyl)phenyl) acetate) 4

heptane-1,7-diylbis(4- (isoquinolin-5- ylsulfonyl)-1,4- diazepane-1-carboxylate) 5

cyclohexane-1,4- diylbis(methylene) (2S,2′S)-bis(2-amino-3- (3,4-dihydroxyphenyl) propanoate) 6

2,2′-(((3,14-dioxo- 2,4,7,10,13,15- hexaoxahexadecane- 1,16-diyl)bis(azanediyl))bis(3- (4-bromobenzoyl)-2,1- phenylene))diaceticacid 7

(ethane-1,2- diylbis(oxy))bis(ethane- 2,1-diyl) bis(2-(1-(4-chlorobenzoyl)-5- methoxy-2-methyl-1H- indol-3-yl)acetate)

Formulations

The pharmaceutical compositions of the disclosure can include an articlein the form of fibers, fiber meshes, woven fabrics, non-woven fabrics,pellets, cylinders, hollow tubes, microparticles, nanoparticles, orother shaped articles. In some embodiments, the pharmaceuticalcomposition of the disclosure has a non-circular shape that affects,e.g., increases, the surface area (e.g., extruded through star-shapeddye or any other form shaping process with or without a dye mold).Suitable pharmaceutical compositions for use with this disclosure can besmall regularly or irregularly shaped particles, which can be solid,porous, or hollow.

Different forms of pharmaceutical compositions of the present disclosure(e.g., fibers, fiber meshes, woven fabrics, non-woven fabrics, pellets,cylinders, hollow tubes, microparticles (e.g., microbeads),nanoparticles (e.g., nanobeads), or other shaped articles) can have theadvantages of providing a controllable surface area, being easilyinjected, not requiring removal after completion of drug release, andallow for tailoring drug release rates required for a given indication.When used as an injectable drug delivery device, drug release rate andinteraction with cells are strongly dependent on the size distributionof the pharmaceutical composition form.

Processing Methods

Articles of the disclosure can be formed using any number of themethods, for example, heat processing or solvent processing of the drugdimer of formula (A-I). Heat processing can include heat molding,injection molding, extrusion, 3D printing, melt electrospinning, fiberspinning, fiber extrusion, and/or blow molding. Solvent processing mayinclude coating, micro printing, dot printing, micropatterning, fiberspinning, solvent blow molding, electrospraying, and electrospinning.Processing methods to form an intermediate glassy state may be any ofthe above heat and solvent based methods as well as heat and solventbased methods that lead to glassy state material with no defined shape(e.g. spray drying, lyophilization, powder melting, etc.).

Electrospraying

In some embodiments, the pharmaceutical compositions of the disclosureare dissolved in a solvent (e.g., acetone) at concentrations rangingfrom, e.g., 10-30% w/v, and are electrosprayed to form micro- andnanobeads. The solutions can be loaded into a syringe and can beinjected at a particular rate, e.g., 0.5 mL/h, onto a stationarycollection plate. Between the needle and collecting surface, a potentialdifference of, e.g., 18 kV, can be maintained. Exemplary concentrationof 10% w/v is used to obtain nanoparticles. In other embodiments, aconcentration of 30% w/v is used to obtain microbeads.

Fiber Spinning

In some embodiments, the pharmaceutical compositions of the disclosure,e.g., fibrous meshes with aligned and unaligned morphologies areprepared by electrospinning. The pharmaceutical compositions of thedisclosure are dissolved in a solvent (e.g., THF, or 1:1 ratio ofDCM/THF). The solutions may be injected from a syringe at a particularrate, e.g., 0.5 mL/h, onto a cylindrical mandrel rotating at aparticular rotational speed, e.g., 1150 rpm, to obtain aligned fibers,or onto a stationary collector surface to obtain unaligned fibers. Apotential difference (e.g., 18 kV or 17 kV) can be maintained betweenthe needle and collecting surface for aligned and random fibers.

In other embodiments, fibers are prepared either from the melt atelevated temperatures, the glassy state intermediate, or from solutionby dissolving the pharmaceutical compositions of the disclosure in asolvent (e.g., DCM, THF, or chloroform). As used herein, melt spinningdescribes heat processing from the melt state, heat spinning describesheat processing from the glassy state, and wet, dry, and gel spinningdescribe solution processing.

The viscous melt, intermediate, or solution can be fed through aspinneret and fibers may be formed upon cooling (melt or heat spinning)or following solvent evaporation with warm air as the compound exits thespinneret (dry spinning). Wet spinning and gel spinning, performedaccording to methods known in the art, may also be used to produce thefibers of the disclosure. Heat spinning describes a process that isessentially the same as the melt spinning process, but performed withthe glassy state intermediate and heated above the glass transitiontemperature (Tg) to get the viscous fluid to extrude/spin instead of themelt. Alternatively, tweezers may be dipped into melted material orconcentrated solutions and retracted slowly in order to pull fibers. Therate of pulling and distance pulled may be varied to yield fibers andcolumnar structures of different thickness.

Emulsion

In some embodiments, micro-particles or nano-particles made from thepharmaceutical composition can be formed using an emulsion process. Thepharmaceutical composition may be dissolved in an organic solvent (e.g.DCM, THF, etc.) and a surfactant (e.g. SDS, PVA, etc.) may be added tothe solution/mixture at a low percentage (e.g. 1%). The resultingmixture may be stirred for the appropriate time at room temperature toform an emulsion. The emulsion may be subsequently added to Milli-Qwater under stirring for an appropriate time (e.g. 1 h) to removeresidual solvent. The resulting micro- or nano-particles may becollected by centrifugation and dried to obtain the desired form.

Extrusion

In some embodiments, injectable cylinders made from the pharmaceuticalcomposition may be formed by heat extrusion. The pharmaceuticalcomposition may be loaded into a hot melt extruder, heated to atemperature above the melting point (for crystalline compositions) orglass transition temperature (for pre-melted or amorphous compositions),and extruded using a light compressive force to push the materialthrough the nozzle and a light tensile force to pull the material out ofthe extruder. The extrudate may be cut to the desired length forappropriate drug dosing for the indication of interest.

Bead Sizing and Milling

In some embodiments, a milling process may be used to reduce the size ofan article of the disclosure to form sized particles, e.g., beads, inthe micrometer (microbeads) to nanometer size range (nanobeads). Themilling process may be performed using a mill or other suitableapparatus. Dry and wet milling processes such as jet milling,cryo-milling, ball milling, media milling, sonication, andhomogenization are known and can be used in methods described herein.Generally, in a wet milling process, a suspension of the material to beused as the core is agitated with or without excipients to reduceparticle size. Dry milling is a process wherein the material to be usedas the article core is mixed with milling media with or withoutexcipients to reduce particle size. In a cyro-milling process, asuspension of the material to be used as the core is mixed with millingmedia with or without excipients under cooled temperatures. In someembodiments, subsequent heating of the milled microparticle above the Tgis needed to achieve a spherical shape, or particles with non-sphericalshapes can be used as milled.

Low Temperature Processing Using Intermediate Glassy State Articles

In certain embodiments, the prodrug dimer has a limited window (e.g.,short timeframe of seconds to minutes) of thermal stability, whereby thepurity of the dimer is minimally affected at elevated temperatures. Insome embodiments, it is beneficial to make an intermediate glassy stateform (e.g., film, surface coating, pellet, micro-particles, or othershaped article). This can be accomplished by heat or solvent processingto remove or reduce the crystallinity of the material to form a glassystate composition. The glassy state composition is subsequently heatprocessed at a lower temperature (e.g., processing just above the glasstransition temperature (Tg), and below the melt temperature (Tm)). Thiscan provide a longer timeframe for heat processing the glassy statematerial into the final shaped article, while reducing the impact ofprocessing conditions on the purity of the prodrug dimer in the article.

Exemplary processing details are provided in the Examples.

Drug Delivery

The pharmaceutical compositions of the disclosure provide optimaldelivery of a drug as they release the drug from an article of thedisclosure in a controlled manner, for example, by surface erosion. Thesurface erosion mechanism of drug release may allow the shaped articleto maintain its physical form, while gradually decreasing in size as thesurface erodes (e.g., like a bar of soap), rather than bulk erosion thatis characteristic of some polymer-based drug release vehicles (e.g.,polylactic/glycolic acid). This may inhibit burst release and reduce theformation of inflammatory particulates (e.g., no or minimal crystallineparticulates are formed or released from the articles when drug isreleased in the manner described herein). The drug can be controlled tobe delivered over a desired period of time. A slower and steadier rateof delivery (e.g., release of less than 10% of D1 or D2 (as a percentageof the total drug, D1 or D2, present in the fiber in prodrug form) at37° C. in 100% bovine serum over 5 days) may in turn result in areduction in the frequency with which the pharmaceutical compositionmust be administered to a subject, and improve the safety profile of thedrug. Drug release can also be tailored to avoid side effects of slowerand longer release of the drug by engineering the article to providesteady release over a comparatively shorter period of time. Depending onthe indication and the drug, the drug release can be tailored for doseand duration appropriate to the indication of interest.

The rate of release of a drug can depend on many factors, for example,the drug composition of the drug dimer. Drug release rate from theformed object of the drug dimer can be modulated by the cleavage ofdrug-linker bond through hydrolysis or enzymatic degradation. Therefore,the selection of linking moiety can affect drug release rate. Further,the drug release rate can be controlled by the selection of thefunctional group on the drug to conjugate through to the linker, forexample, a primary vs. a secondary hydroxyl group. The rate of releaseof a given drug from a drug dimer may also depend on the quantity of theloaded drug dimer as a percent of the final drug dimer formulation,e.g., by using a pharmaceutical excipient (e.g., bulkingagent/excipient). Another factor that can affect the release rate of adrug from, for example a microbead, is the microbead size. In someembodiments, drug release is tailored based on the solubility of drugdimer (e.g., through selection of appropriate drug and/or linker) thatwill influence the rate of surface erosion (e.g.,dissolution/degradation) from the article. In other embodiments, drugrelease is affected by changes in surface area of the formulation, e.g.,by changing the diameter of the microbeads. By adjusting the vide suprafactors, dissolution, degradation, diffusion, and controlled release maybe varied over wide ranges. For example, release may be designed to beinitiated over minutes to hours, and may extend over the course of days,weeks, months, or years.

Uses and Pharmaceutical Compositions

In some embodiments, the drug dimers of the disclosure are used as adrug delivery device (or, e.g., a drug depot) with a minimal need foradditives. This may achieve a local, sustained release and a localbiological effect, while minimizing a systemic response. In someembodiments, when present, the additives are in small amounts and do notaffect the physical or bulk properties. In some embodiments, whenpresent, the additives do not alter the drug release properties from thepharmaceutical composition but rather act to improve processing of theprodrug dimer into the shaped article. In some embodiments, thepharmaceutical compositions contain additives such as a plasticizer(e.g., to reduce thermal transition temperatures), an antioxidant (e.g.,to increase stability during heat processing), a binder (e.g., to addflexibility to the fibers), a bulking agent (e.g., to reduce total drugcontent), a lubricant, a radio-opaque agent, or mixtures thereof. Theadditives may be present at 30% (w/w), e.g., 20% (w/w), 10% (w/w), 7%(w/w), 5% (w/w), 3% (w/w), 1% (w/w), 0.5% (w/w), or 0.1% (w/w). Examplesof plasticizers are polyols, e.g., glycerol, ethylene glycol, diethyleneglycol, triethylene glycol, tetraethylene glycol, polyethylene glycol,propylene glycol, triacetin, sorbitol, mannitol, xylitol, fatty acids,monosaccharides (e.g., glucose, mannose, fructose, sucrose),ethanolamine, urea, triethanolamine, vegetable oils, lecithin, or waxes.Exemplary antioxidants are glutathione, ascorbic acid, cysteine, ortocopherol. The binders and bulking agents can be, e.g.,polyvvinylpyrrolidone (PVP), starch paste, pregelatinized starch,hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC), orpolyethylene glycol (PEG) 6000.

Methods involving treating a subject may include preventing a disease,disorder or condition from occurring in the subject which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected (e.g.,such treating the pain of a subject by administration of an agent eventhough such agent does not treat the cause of the pain).

Pharmaceutical compositions containing the drug dimers described hereinmay be administered to a subject via any route known in the art. Theseinclude, but are not limited to, oral, sublingual, nasal, intradermal,subcutaneous, intramuscular, rectal, vaginal, intravenous,intraarterial, intracisternally, intraperitoneal, intravitreal,periocular, topical (as by powders, creams, ointments, or drops), buccaland inhalational administration. Desirably, the articles of thedisclosure are administered parenterally as injections (intravenous,intramuscular, or subcutaneous), or locally as injections (intraocularlyor into a joint space). The formulations are admixed under sterileconditions with a pharmaceutically acceptable carrier and any neededpreservatives or buffers as may be required.

The articles provided herein may be administered to a subject to bedelivered in an amount sufficient to deliver to a subject atherapeutically effective amount of an incorporated pharmaceutical agentas part of prophylactic or therapeutic treatment, or as a part ofadjunctive therapy to avoid side-effects of another drug or therapy. Ingeneral, an effective amount of a pharmaceutical agent or componentrefers to the amount necessary to elicit the desired biologicalresponse. The desired concentration of pharmaceutical agent in thearticle of the disclosure will depend on numerous factors, including,but not limited to, absorption, inactivation, and excretion rates of thedrug as well as the delivery rate of the compound from the subjectcompositions, the desired biological endpoint, the agent to bedelivered, the target tissue, etc. It is to be noted that dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions. Typically, dosingwill be determined using techniques known to one skilled in the art.

The concentration and/or amount of any pharmaceutical agent to beadministered to a subject may be readily determined by one of ordinaryskill in the art. Known methods are also available to assay local tissueconcentrations, diffusion rates from drug dimers and local blood flowbefore and after administration of the therapeutic formulation.

Sterilization of Formulations

Generally, it is desired that a formulation is sterile before or uponadministration to a subject. A sterile formulation is essentially freeof pathogenic microorganisms, such as bacteria, microbes, fungi,viruses, spores, yeasts, molds, and others generally associated withinfections. In some embodiments, articles of the disclosure may besubject to an aseptic process and/or other sterilization process. Anaseptic process typically involves sterilizing the components of aformulation, final formulation, and/or container closure of a drugproduct through a process such as heat, gamma irradiation, ethyleneoxide, or filtration and then combining in a sterile environment. Insome cases, an aseptic process is preferred. In other embodiments,terminal sterilization is preferred.

Treatment Methods

The formulations of the disclosure may be used in the fields ofophthalmology, oncology, laryngology, endocrinology and metabolicdiseases, rheumatology, urology, neurology, cardiology, dental medicine,dermatology, otology, post-surgical medicine, orthopedics, painmanagement, and gynecology. In some embodiments, a formulation providedherein may be used to treat a CNS disease or disorder.

The compound of the disclosure can be selected for the desired property,such as a nonsteroidal anti-inflammatory drug (NSAID) dimers for the usein treating inflammation, pain management, knee osteoarthritis,postoperative pain; (e.g., opioid) analgesic dimers for the use ofchronic pain treatment; CNS agent dimers for the use of treatingParkinson's Disease or in ophthalmology; ROCK inhibitor dimers for theuse of treating glaucoma, asthma, cancer, insulin resistance, orosteoporosis; anthraquinone dimers for the use of treatingosteoarthritis; anti-cancer agent dimers for the use of chemotherapy andtreating cancer; antiviral agent dimers for treating or preventing viralinfections; and antioxidant dimers for the use of treating inflammation,cancer, as a neural protective agent, and as an antiatherogenic agent

EXAMPLES

The following examples are put forth to provide those of ordinary skillin the art with a description of how the compositions and methodsdescribed herein may be used, made, and evaluated, and are intended tobe purely exemplary of the invention and are not intended to limit thescope of what the inventors regard as their invention.

1. Analytical Methods Analytical Example 1: High Performance LiquidChromatography (HPLC)

Samples (20.0 mg) were dissolved in acetonitrile (10.0 mL) to make 2mg/mL solutions. The samples were loaded onto an Agilent 1260 SeriesHPLC with a Phenomenex Gemini-NX C18 Column (5 μm; 110 Å; 250×4.6 mm;00G-4454-E0) equipped with a Phenomenex SecurityGuard Analytical GuardPre-Column (KJO-4282) containing Gemini C18 4×3.0 mm Guard Cartridge(AJO-7597). For the system: solvent A was Water+0.05% trifluoroaceticacid (TFA); solvent B was Acetonitrile+0.05% TFA; the flow rate was 1.0mL/min and the injection volume was 5 μL. Solvent gradient profiles weredesignated as either Method 1 or Method 2, with the details shown inTables 2 and 3 respectively. Detection method was UV @242 nm (LowPolarity) or UV @296 nm (Timolol), with UV Spectra from 190 to 400 nmcollected in both cases.

TABLE 2 Method 1 Time % A % B (min) Solvent Solvent  0 80  20 40 16  8442  0 100 50  0 100

TABLE 3 Method 2 Time % A % B (min) Solvent Solvent  0 98  2 30 68  3235  0 100 45  0 100

Method 3: Samples (20.0 mg) were dissolved in methanol (10.0 mL) to make2 mg/mL solutions. For the system: solvent A was 90% 10 mM potassiumphosphate buffer (pH 6.6)+10% methanol (v/v); solvent B was 90%methanol+10% 10 mM potassium phosphate buffer (pH 6.6) (v/v); the flowrate was 1.0 mL/min and injection volume was 5 μL; detection method wasUV @220 nm and UV Spectra from 190 to 400 nm. The samples were loadedonto an Agilent 1200 series HPLC with a Phenomenex Gemini-NX C18 Column(5 μm; 110 Å; 250×4.6 mm; OOG-4454-E0) equipped with a PhenomenexSecurityGuard Analytical Guard Pre-Column (KJO-4282) containing GeminiC18 4×3.0 mm Guard Cartridge (AJO-7597). The solvent gradient profile isshown in Table 4:

TABLE 4 Time % A % B (min) Solvent Solvent 0.0 50  50 3.5 15  85 9.5  0100 26.5   0 100 32.5  50  50 40.0  50  50

Analytical Example 2: Nuclear Magnetic Resonance (NMR)

Compounds (10 mg) were dissolved in 666 μL of either CDCl₃ or DMSO-d6and loaded in an 8-inch length, 5 mm diameter NMR tube. The instrumentwas a Varian Mercury 400 NMR spectrometer. Proton NMR spectra wereobtained with 16 scans using the default method. FIDs were processedwith MestRe-C software.

Analytical Example 3: Mass Spectrometry (MS)

Compounds were dissolved in acetonitrile at 1 mg/ml and used directlyfor analysis on an Agilent 6538 QTOF, using ESI MS+ as ion source.

Analytical Example 4: Melting Point

Compound powder was prepared neat in a glass capillary tube, and meltingtemperature was measured manually with standard glass capillary tubemelting point apparatus.

Analytical Example 5: Differential Scanning Calorimetry

5-10 mg of compounds were weighed in an aluminum pan. Using a HitachiDifferential Scanning Calorimeter DSC7020, samples were heated from roomtemperature to 110-280° C. at 10° C./min, cooled to −30° C. at 10°C./min, and heated again to 110-280° C. at 10° C./min.

Analytical Example 6: Light Microscopy

Heat molded pellets were imaged using a Leica DMV6 light microscopeequipped with Leica application suite X software.

II. Chemical Synthesis

Solvents, reagents and starting materials were purchased from commercialvendors and used as received unless otherwise described. All reactionswere performed at room temperature unless otherwise stated. Startingmaterials were purchased from commercial sources or synthesizedaccording to the methods described herein or using literatureprocedures.

Chemical Synthesis Example 1

Compound 1 (Dexamethasone-Triethylene Glycol-Dexamethasone) can beSynthesized, Processed into Pellets in the Glassy State by Heat Molding,and Release Drug Through Surface Erosion from an Intact Pellet

Dexamethasone (1 mol equivalent) was suspended in dichloromethane on anice bath and triethylamine (2 mol equivalent) and triethylene glycolbis(chloroformate) (0.6 mol equivalent) were added to the mixture. Theice bath was allowed to warm to room temperature and the reaction wasstirred overnight. The solvent was removed and the solid residue waspurified by column chromatography. Product was recrystallized twice fromacetonitrile to give Compound 1 (FIG. 1A) as an off-white crystallinesolid.

Compound 1: HPLC (Method 1) 31.7 min; Elemental analysis: Anal. Calcdfor C₅₂H₆₈F₂O₁₆: C, 63.27; H, 6.94; N, 0.00; Cl, 0.00 Found: C, 62.62;H, 6.84; N, <0.50; Cl<100 ppm. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 0.80(d, J=7 Hz, 6H, 2×C16 α-CH₃); 0.90 (s, 6H, 2×C18-CH₃); 1.08 (m, 2H,2×C16-H); 1.35 (m, 2H, 2×C14-H); 1.49 (s, 6H, 2×C19-CH₃); 1.54 (q, J=13Hz, 2H, 2×C13-H); 1.64 (q, J=11 Hz, 2H, 2×C15-CH₂); 1.77 (m, 2H,2×C15-CH₂); 2.15 (m, 4H, 2×C6-CH₂); 2.32 (m, 4H, 2×C7-CH₂); 2.62 (m, 2H,2×C12-CH₂); 2.89 (m, 2H, 2×C12-CH₂); 3.57 (s, 4H, 2×TEG OCH₂); 3.65 (m,4H, 2×TEG OCH₂); 4.15 (m, 2H, 2×OCH); 4.22 (m, 4H, 2×TEG OCH₂); 4.79 (d,2H, AB, J=18.5 Hz, 2H, C21-CH₂O—); 5.09 (d, 2H, AB, J=18.5 Hz, 2H,C21-CH₂O—); 5.18 (s, 2H, C17-OH); 5.40 (d, 2H, J=4.5 Hz, C11-OH); 6.01(d, 2H, J=1.9 Hz, 2×alkene C4-CH); 6.23 (dd, 2H, J=10.1 and 1.9 Hz, CH,2×alkene C2-CH); 7.29 (d, 2H, C1-CH 2×alkene CH, 10.1 Hz, 2H). MS (ESI+)m/z: [M+H]+ Calcd for C₅₂H₆₉F₂O₁₆ 987.46; Found 987.46.

Compound 1 was formed into pellets in the glassy state by heat molding(FIG. 1B). Crystalline powder was melted at 185° C. and pellets wereformed from 1 mm×1 mm cylindrical molds. The starting powder andheat-processed pellets were tested by differential scanning calorimetry(DSC; FIG. 1C) and X-ray powder diffraction (XRPD; FIG. 1D) to confirmheat-processing converted Compound 1 from the crystalline state to theglassy state.

Heat-molded pellets from Compound 1 (˜1 mm×1 mm) were then placed in 20mL glass vials and 2 mL of release buffer (either 100% phosphatebuffered saline (PBS), 1% fetal bovine serum (FBS) in PBS, or 100% FBS)was added. Samples were incubated at 37° C. on a shaker rotating at 115rpm. After 1 day, 3 days, 7 days, and subsequently in alternating 3 and4 day intervals (i.e., 1, 3, 7, 10, 14 days etc.), release buffer wassampled directly (PBS) or syringe filtered, proteins were precipitatedwith acetonitrile, and drug release products were extracted. The sampleswere analyzed by high performance liquid chromatography (HPLC) toquantify drug products. Cumulative drug release was calculated andplotted as a percentage of the total drug in each pellet released overtime (FIG. 1E). Representative images of the pellets confirm surfaceerosion over time in 100% FBS (FIG. 1F)

Chemical Synthesis Example 2(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(2-(4-(1-oxoisoindolin-2-yl)phenyl)propanoate)(Indoprofen-TEG-Indoprofen, Compound 2)

To a solution of indoprofen (883 mg, 3.14 mmol, 2.00 eq) in DMF (20 mL)was added K₂CO₃ (434 mg, 3.14 mmol, 2.00 eq) and triethylene glycoldi(p-toluenesulfonate) (0.72 g, 1.57 mmol, 1.00 eq). The mixture wasstirred at 80° C. for 3 h, after which the mixture was poured into water(150 mL) and extracted with ethyl acetate (3×20 mL). The combinedorganic phase was washed with water (3×50 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the crude product.This was purified by reversed-phase HPLC to provide the product (460 mg,43%) as an off-white solid. Melting point: 104° C. HPLC (Method 2) 33.4min; ¹H NMR (400 MHz, CDCl₃) δ (ppm) 7.92 (d, J=7.60 Hz, 2H), 7.81 (d,J=8.40 Hz, 4H), 7.56-7.64 (m, 2H), 7.47-7.55 (m, 4H), 7.36 (d, J=8.40Hz, 4H), 4.83 (s, 4H), 4.14-4.33 (m, 4H), 3.76 (q, J=7.20 Hz, 2H), 3.64(t, J=4.40 Hz, 4H), 3.54 (s, 4H), 1.52 (s, 3H), 1.50 (s, 3H). LCMS m/z:[M+H]+ Calcd for C₄₀H₄₁N₂O₈ 677.29; Found 677.2.

Chemical Synthesis Example 3 heptane-1,7-diylbis(4-(isoquinolin-5-ylsulfonyl)-1,4-diazepane-1-carboxylate)(Fasudil-Hep-Fasudil, Compound 3)

A solution of 1,7-heptanediol bis(chloroformate) (501 mg, 1.95 mmol,1.00 eq), fasudil hydrochloride (1.28 g, 3.89 mmol) and TEA (985 mg,9.73 mmol, 1.35 mL, 5.00 eq) in DMF (2 mL) was stirred at 25° C. for 2h. The reaction mixture was poured into H2O (200 mL) and extracted withethyl acetate (3×60 mL). The combined organic phase was washed withbrine (3×100 mL), dried with anhydrous Na2SO4, filtered and concentratedin vacuo to give the crude product which was purified by reversed-phaseHPLC to give compound 3 as a white gum (586 mg, 39%). HPLC retentiontime (Method 2): 34.6 min; 1H NMR (400 MHz, CDCl3) δ (ppm) 9.36 (s, 2H),8.70 (d, J=6.40 Hz, 2H), 8.40 (d, J=6.40 Hz, 2H) 8.30-8.36 (m, 2H), 8.21(d, J=8.00 Hz, 2H), 7.70 (t, J=7.76 Hz, 2H) 4.02 (t, J=6.80 Hz, 4H),3.52-3.63 (m, 8H), 3.38-3.47 (m, 8H), 1.92-2.00 (m, 4H), 1.59 (br s,4H), 1.32 (br s, 6H). LCMS m/z: [M+H]+ Calcd for C37H47N6O8S2 767.29;Found 767.1.

Chemical Synthesis Example 4(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(2-(2-amino-3-(4-bromobenzoyl)phenyl)acetate)(Bromfenac-TEG-Bromfenac, Compound 4)

To a solution of triethylene glycol di(p-toluenesulfonate) (700 mg, 1.53mmol, 1.00 eq) in DMF (20 mL) was added bromfenac sodium (1.02 g, 3.05mmol, 2.0 eq). The mixture was stirred at 50° C. for 10 h. The reactionmixture was poured into water (150 mL) and extracted with ethyl acetate(3×60 mL). The combined organic phase was washed with water (3×100 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe crude product which was purified by reversed-phase HPLC to giveCompound 4 as a yellow gum (572 mg, 47%). HPLC (Method 2) 38.9 min; ¹HNMR (400 MHz, DMSO-d6); δ (ppm) 7.71 (br d, J=8.40 Hz, 4H), 7.49 (br d,J=8.40 Hz, 4H), 7.24 (br dd, J=19.20, 7.53 Hz, 4H), 6.98 (br s, 4H),6.47-6.60 (m, 2H), 4.12-4.21 (m, 4H), 3.70 (s, 4H), 3.60-3.65 (m, 4H),3.51 (s, 4H). LCMS m/z: [M+H]+ Calcd for C36H35Br2N2O8 781.08; Found782.9.

Chemical Synthesis Example 51,10-bis(4-(isoquinolin-5-ylsulfonyl)-1,4-diazepan-1-yl)decane-1,10-dione(Fasudil-Seb-Fasudil, Compound 5)

To a solution of fasudil hydrochloride (1.51 g, 4.60 mmol, 2.0 eq.) andTEA (582 mg, 5.75 mmol, 800 uL, 2.5 eq) in THF (30 mL) was addedsebacoyl chloride (0.55 g, 2.30 mmol, 1.0 eq) and DMAP (56.2 mg, 460umol, 0.2 eq) at 0° C. The mixture was stirred at 20° C. for 2 h afterwhich the mixture was filtered and the filtrate was concentrated invacuo to give the crude product. This was purified by reversed-phaseHPLC to give compound 5 as a light yellow gum (520 mg, 30%). HPLCretention time (Method 2): 33.9 min; ¹H NMR (400 MHz, CDCl₃) δ (ppm)9.27-9.41 (m, 2H), 8.64-8.75 (m, 2H), 8.40 (d, J=6.00 Hz, 2H), 8.30-8.36(m, 2H), 8.16-8.25 (m, 2H), 7.64-7.77 (m, 2H), 3.54-3.78 (m, 9H),3.32-3.53 (m, 9H), 2.24 (br t, J=7.20 Hz, 4H), 1.95-2.02 (m, 4H),1.23-1.33 (m, 10H). LCMS m/z: [M+H]+ Calcd for C₃₈H₄₉N₆O₆S₂ 749.32;Found 749.3.

Chemical Synthesis Example 6 cyclohexane-1,4-diylbis(methylene)(2S,2′S)-bis(2-amino-3-(3,4-dihydroxyphenyl)propanoate)(L-Dopa-CDM-L-Dopa, Compound 6)

A solution of dibenzyl-Boc-L-DOPA (8.74 g, 18.3 mmol, 2.40 eq),1,4-Cyclohexanedimethanol (1.10 g, 7.63 mmol, 1.00 eq.) and DPTS (449mg, 1.53 mmol, 0.20 eq) in DCM (100 mL) was stirred at 0° C. After allthe solids were dissolved DIC (27.0 g, 214 mmol, 33.1 mL, 28.0 eq) wasadded in one portion and the mixture was stirred at 25° C. for 6 h underN₂. The reaction mixture was filtered and the filtrate was concentratedin vacuo to give the crude product which was purified by columnchromatography (SiO₂, Petroleum ether: Ethyl acetate=5:1 to 0:1, TLC,Petroleum ether: Ethyl acetate=3:1, the product R_(f)=0.5) to give theproduct (10.0 g, crude) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ(ppm) 7.40-7.49 (m, 8H), 7.27-7.40 (m, 12H), 6.86 (d, J=8.40 Hz, 2H),6.75 (d, J=1.60 Hz, 2H), 6.64 (dd, J=8.40, 1.63 Hz, 2H), 5.11 (s, 8H),4.94 (br d, J=7.20 Hz, 2H), 4.52 (br d, J=7.20 Hz, 2H), 4.05-4.18 (m,6H), 2.98 (br s, 4H), 1.71 (s, 6H), 1.38-1.47 (m, 18H).

A mixture of 1,4-cyclohexanedimethanol bis(dibenzyl-Boc-L-DOPA) ester(10.0 g, 9.40 mmol, 1.00 eq) and Pd/C (2.00 g, 9.40 mmol, 1.0 eq) in THF(100 mL) was degassed and purged with H₂ 3 times, the mixture wasstirred at 20° C. for 6 h under H₂ atmosphere (50 psi). The reactionmixture was filtered and concentrated in vacuo to give the intermediate1,4-cyclohexanedimethanol bis(Boc-L-DOPA) ester (10.0 g, crude) as ayellow oil without further purification which was used in the next step.

A solution of 1,4-cyclohexanedimethanol bis(Boc-L-DOPA) ester (10.0 g,14.2 mmol, 1.00 eq) and HCl/dioxane (4 M, 150 mL, 42.2 eq) in dioxane(20 mL) was stirred at 25° C. for 2 h. The reaction mixture wasconcentrated in vacuo and the pH was adjusted to pH 8 with sat.NaHCO₃.The mixture was extracted with ethyl acetate (3×100 mL). The combinedorganic phase was washed with brine (2×100 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the crude productwhich was purified by reversed phase prep-HPLC to give the product solnwhich was adjusted to pH 8 with sat.NaHCO₃. The mixture was extractedwith ethyl acetate (3×100 mL). The combined organic phase was washedwith brine (2×100 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give compound 6 as a light yellow solid (449mg, 893 umol, 6.3%). HPLC (Method 2) 18.8 min; Melting point: 161-166°C.; ¹H NMR (400 MHz, MeOD) δ (ppm) 6.68 (d, J=8.00 Hz, 2H), 6.60 (d,J=2.00 Hz, 2H), 6.49 (dd, J=8.00, 2.02 Hz, 2H), 3.79-3.94 (m, 4H), 3.63(t, J=6.40 Hz, 2H), 2.81 (dd, J=6.40, 3.55 Hz, 4H), 1.64 (br t, J=7.60Hz, 4H), 1.37-1.53 (m, 2H), 0.82-0.97 (m, 4H). LCMS m/z: [M+H]+ Calcdfor C₂₆H₃₅N₂O₈ 503.2; Found 503.2.

Chemical Synthesis Example 72,2′-(((3,14-dioxo-2,4,7,10,13,15-hexaoxahexadecane-1,16-diyl)bis(azanediyl))bis(3-(4-bromobenzoyl)-2,1-phenylene))diaceticacid (Bromfenac-TEG-Bromfenac—formaldehyde Bridge, Compound 7)

Chloromethyl chloroformate (2.94 ml, 33.1 mmol) is added to an ice-coldsolution of triethyleneglycol (2.22 ml, 16.5 mmol) in dichloromethane(30 ml) followed by pyridine (5.33 ml, 66.2 mmol) at such a rate thatthe temperature is kept below 10° C. After stirring overnight at roomtemperature the reaction mixture is washed twice with 0.5 M HCl followedby water and aqueous sodium bicarbonate. The organic layer is dried(MgSO4) and concentrated in vacuo to give triethyleneglycolbis(chloromethyl carbonate) (11.1 g, 33.1 mmol) as a colorless oil.

To a solution of bromfenac (2.12 g, 6.62 mmol) in DMF (20 mL) is addedpotassium carbonate (0.91 g, 6.62 mmol) and triethyleneglycolbis(chloromethyl carbonate) (1.11 g, 3.31 mmol). The mixture is heatedto 100° C. for 2 h. The reaction mixture is diluted with water (200 mL)and extracted with DCM (2×200 mL). The DCM layers are combined andwashed with water (5×400 mL), dried (MgSO₄) and concentrated in vacuo togive the crude product (Compound 7).

Chemical Synthesis Example 8(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetate)(Indomethacin-TEG-Indomethacin, Compound 8)

To a stirred solution of (1.073 g, 3.0 mmol) in dry DCM (100 mL) undernitrogen was added 4-(dimethylamino)pyridine (732 mg, 6.0 mmol),triethyleneglycol (225 mg, 1.5 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.15 g,6.0 mmol) and the mixture was stirred overnight. The mixture wasconcentrated onto 5 g normal phase silica. Purification was performed bynormal phase automated chromatography (ethyl acetate-hexane). Productcontaining fractions were combined and concentrated to give compound 8as an off-white solid (759 mg, 61%). Melting point: 102° C. HPLCretention time (Method 1): 44.1 min, ESI MS+ Found, C₄₄H₄₂Cl₂N₂NaO₁₀ ⁺Mass: 851.21 ¹H NMR (400 MHz, DMSO-d6) δ (ppm); 7.82 (m, 8H), 7.01 (s,2H), 6.92 (d, J=8.0 Hz, 2H), 6.65 (d, J=8.0 Hz, 2H), 4.12 (m, 4H), 3.65(m, 10H), 3.54 (m, 4H), 3.41 (s, 4H), 2.19 (s, 6H).

Chemical Synthesis Example 9 Procedure for Preparation of Drug DimerForm Enolizable Ketone Functional Group

Compounds bearing an enolizable ketone can be prepared by reaction withlithium diisopropylamide in tetrahydrofuran to drive the enol tautomerto the formation of the lithium enolate, followed by reaction with anappropriate linking moiety to form the drug dimer. An exemplary reactionscheme (Scheme 1) is shown below where the compound is formed fromhydromorphone and the linkage group is a carbonate.

Chemical Synthesis Example 10bis((4R,4aS,7aR,12bS)-4a-hydroxy-9-methoxy-3-methyl-2,3,4,4a,5,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)adipate. Compound A)

Dimeric compositions bearing an enolizable ketone (e.g., oxycodone) areprepared by reaction with lithium diisopropylamide (LDA, 2 equiv.) intetrahydrofuran at −78° C. for 5 min to 1 hr, driving the enol tautomerto the formation of the lithium enolate. The appropriate linkerprecursor (e.g., adipoyl chloride, 0.5 eq.) is added and the reaction isstirred for 1 hr to 16 hrs at room temperature to form the drug dimer(e.g., oxycodone-adip-oxycodone).

Chemical Synthesis Example 11bis((4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)adipate (naloxone-adipate-naloxone ester, Compound 9)

To a stirred suspension of naloxone hydrochloride (250 mg, 0.687 mmol)in dry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine(168 mg, 1.374 mmol), adipic acid (50 mg, 0.343 mmol) andN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (263 mg,1.374 mmol) and the mixture was stirred overnight. The mixture wasconcentrated onto 2 g reverse phase silica. Purification was performedby reverse phase chromatography (aqueous-MeCN gradient). Productcontaining fractions were combined, extracted with DCM, dried (MgSO₄)and concentrated to give Compound 9 as an off-white solid (100 mg, 38%).Melting point: 120° C.; HPLC (Method 1) retention time: 6.75 min; ESIMS+ Found, C₄₄H₄₈N₂NaO₁₀ ⁺, Mass: 787.32 g/mol; ¹H NMR (400 MHz,DMSO-d₆) δ 6.82 (2H, d, J=8.0 Hz); 6.74 (2H, d, J=8.0 Hz); 5.82 (2H, m,(3-CH allyl); 5.21 (2H, d, J=16.8 Hz, γ-CH-allyl, trans); 5.12 (2H, d,J=10.0 Hz, γ-CH-allyl, cis); 5.04 (2H, s); 4.85 (2H, s); 3.10 (6H, m);2.85 (6H, m); 2.54 (6H, m); 2.32 (2H, m); 2.03 (2H, m); 1.95 (2H, m);1.74 (6H, m); 1.43 (2H, m); 1.22 (2H, m).

Chemical Synthesis Example 12bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)adipate (naltrexone-adipate-naltrexone, Compound 10)

To a solution of naltrexone hydrochloride (1.63 g, 4.31 mmol) in DCM(120 mL) under nitrogen was added 4-(dimethylamino)pyridine (1.00 g,8.21 mmol), adipic acid (300 mg, 2.05 mmol) anddimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (1.57 g, 8.21mmol, 4.00 eq) at 0° C. The mixture was stirred at 25° C. for 8 h. Thereaction mixture was concentrated under reduced pressure to give aresidue. The crude product was purified by reversed-phase HPLC (column:Agela DuraShell C18 250*50 mm*10 um; mobile phase: [water (0.05%NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 55%-85%, 20 min) to give the product asan off-white solid (658 mg, 60%). Melting point: 187° C. HPLC (Method 3)retention time: 7.0 min, ESI MS+ Found, C₄₆H₅₃N₂O₁₀ ⁺ Mass: 793.37 1HNMR (400 MHz, DMSO) δ 6.84 (d, J=8.2 Hz, 2H), 6.72 (d, J=8.3 Hz, 2H),5.15 (s, 1H), 4.92 (s, 2H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s, 1H), 3.05(s, 1H), 2.91 (td, J=14.3, 5.0 Hz, 2H), 2.70-2.52 (m, 8H), 2.38 (tt,J=11.2, 6.3 Hz, 6H), 2.11 (dt, J=12.6, 2.4 Hz, 2H), 1.95 (td, J=12.1,3.8 Hz, 2H), 1.84-1.74 (m, 3H), 1.73 (d, J=3.3 Hz, 2H), 1.45 (td,J=14.0, 3.4 Hz, 2H), 1.33-1.21 (m, 2H), 0.95-0.81 (m, 2H), 0.55-0.42 (m,4H), 0.20-0.07 (m, 4H).

Chemical Synthesis Example 13bis((4R,4aS,7aS,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-methylene-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)adipate, Nalmefene-Adip-Nalmefene, Compound 11)

To a solution of nalmefene (2.44 g, 7.18 mmol) in DCM (100 mL) was added4-(dimethylamino)pyridine (1.25 g, 10.26 mmol), adipic acid (0.500 g,3.42 mmol) and dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride(2.62 g, 13.69 mmol) at 0° C. under N₂ atmosphere. The mixture wasstirred at 20° C. for 10 h. The reaction mixture was concentrated underreduced pressure to give a residue. The crude product was purified byreversed-phase HPLC (column: Welch Xtimate C18 250*70 mm #10 um; mobilephase: [water (0.04% NH₃H₂O+10 mM NH4HCO3)-ACN]; B %: 80%-100%, 300 min)to give the product (1.30 g, 48% yield) as a light yellow solid. Meltingpoint: 87° C. HPLC (Method 3) retention time: 9.0 min, ESI MS+ Found,C₄₈H₅₇N₂O₈ ⁺ Mass: 789.41 ¹H NMR (400 MHz, DMSO) δ 6.75 (d, J=8.11 Hz,2H) 6.63 (d, J=8.11 Hz, 2H) 5.03 (d, J=1.10 Hz, 2H) 4.94 (s, 2H) 4.87(s, 2H) 4.76 (d, J=1.75 Hz, 2H) 3.00 (br dd, J=11.95, 6.69 Hz, 4H)2.48-2.71 (m, 8H) 2.15-2.46 (m, 8H) 1.87-2.07 (m, 4H) 1.64-1.78 (m, 4H)1.43-1.55 (m, 2H) 1.10-1.28 (m, 4H) 0.74-0.89 (m, 2H) 0.36-0.54 (m, 4H)0.00-0.16 (m, 4H)

Chemical Synthesis Example 14bis((4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)decanedioate (Naloxone-Seb-Naloxone, Compound 12)

To a solution of naloxone hydrochloride dihydrate (1.04 g, 2.60 mmol) inDCM (100 mL) under nitrogen was added 4-(dimethylamino)pyridine (604 mg,4.94 mmol), sebacic acid (250 mg, 1.24 mmol) anddimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (948 mg, 4.94mmol) at 0° C. The mixture was stirred at 25° C. for 8 h. The reactionmixture was concentrated under reduced pressure to give a residue. Thecrude product was purified by reversed-phase HPLC (column: AgelaDuraShell C18 250*80 mm*10 um; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 55%-85%, 20 min) to give the product (855 mg, 84%yield) as a white solid. Melting point: 86° C. HPLC (Method 3) retentiontime: 8.8 min, ESI MS+ Found, C₄₈H₅₇N₂O₁₀ ⁺ Mass: 821.40 ¹H NMR (400MHz, DMSO) δ ppm 6.83 (d, J=8.16 Hz, 2H) 6.73 (d, J=8.16 Hz, 2H) 5.86(ddt, J=16.97, 10.38, 6.27, 6.27 Hz, 2H) 5.25 (br d, J=17.19 Hz, 2H)5.15 (br d, J=10.42 Hz, 2H) 5.07 (s, 2H) 4.90 (s, 2H) 3.07-3.20 (m, 6H)2.84-3.00 (m, 4H) 2.52-2.62 (m, 6H) 2.37 (td, J=12.49, 5.02 Hz, 2H)2.09-2.13 (m, 2H) 2.07 (s, 2H) 1.95 (td, J=12.02, 3.45 Hz, 2H) 1.72-1.80(m, 2H) 1.63 (quin, J=7.18 Hz, 4H) 1.25-1.48 (m, 12H)

Chemical Synthesis Example 15bis((4R,4aS,7aR,12bS)-3-allyl-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)(cyclohexane-1,4-diylbis(methylene)) bis(carbonate)(Naloxone-CDM-Naloxone, Compound 13)

To a solution of cyclohexanedimethanol bis(4-nitrophenyl carbonate)(1.00 g, 2.11 mmol, 1.00 eq) and naloxone hydrochloride dihydrate (1.81g, 4.53 mmol, 2.15 eq) in DMF (5 mL) was added diisopropylethylamine(1.63 g, 12.6 mmol, 6.00 eq) and 4-(dimethylamino)pyridine (25.7 mg, 211umol) at 0° C., then stirred at 20° C. for 12 h. The reaction mixturewas poured into water (50 mL), extracted with ethyl acetate (2×50 mL),the organic layer was washed with brine (3×50 mL), dried over Na₂SO₄,filtered and concentrated to give a residue. The residue was purified byprep-HPLC (column: Agela DuraShell C18 250*70 mm*10 um; mobile phase:[water (0.05% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 68%-88%, 20 min) to givethe product (1.00 g, 55% yield) as a light yellow solid. Melting point:126° C. HPLC (Method 3) retention time: 8.3 min, ESI MS+ Found,C₄₈H₅₅N₂O₁₀ ⁺ Mass: 851.38 ¹H NMR (400 MHz, DMSO) δ 6.96 (d, J=8.33 Hz,2H) 6.75 (d, J=8.11 Hz, 2H) 5.86 (ddt, J=16.96, 10.39, 6.17, 6.17 Hz,2H) 5.25 (br d, J=17.32 Hz, 2H) 5.15 (br d, J=10.52 Hz, 2H) 5.08 (s, 2H)4.96 (s, 2H) 3.99-4.18 (m, 4H) 3.07-3.22 (m, 6H) 2.86-3.02 (m, 4H)2.52-2.65 (m, 4H) 2.32-2.45 (m, 2H) 2.10 (br d, J=14.03 Hz, 2H) 1.95(td, J=12.06, 3.51 Hz, 2H) 1.76 (br d, J=8.11 Hz, 6H) 1.64 (br s, 2H)1.37-1.56 (m, 4H) 1.28 (br d, J=10.74 Hz, 2H) 1.03 (br t, J=8.33 Hz,2H).

Chemical Synthesis Example 16bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)decanedioate (Naltrexone-Seb-Naltrexone, Compound 14)

To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) indry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244mg, 2.0 mmol), sebacic acid (101 mg, 0.50 mmol) andN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg,2.00 mmol) and the mixture was stirred overnight. The mixture wasconcentrated onto 2 g reverse phase silica. Purification was performedby reverse phase automated chromatography (aqueous-MeCN gradient).Product containing fractions were combined and concentrated to give theproduct as an off-white solid (294 mg, 69%). Melting point: 86° C. HPLC(Method 3) retention time: 8.9 min, ESI MS+ Found, C₅₀H₆₁N₂O₁₀ ⁺ Mass:849.43 ¹H NMR (400 MHz, DMSO) δ 6.82 (d, J=8.2 Hz, 2H), 6.71 (d, J=8.2Hz, 2H), 5.14 (s, 2H), 4.91 (s, 2H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s,2H), 3.04 (s, 2H), 2.97-2.84 (m, 4H), 2.67 (dd, J=12.0, 5.0 Hz, 2H),2.64-2.51 (m, 8H), 2.44-2.31 (m, 6H), 2.15-2.05 (m, 4H), 1.95 (td,J=12.1, 3.8 Hz, 2H), 1.79 (dd, J=13.6, 4.8 Hz, 2H), 1.63 (p, J=7.2 Hz,4H), 1.46 (dd, J=14.0, 3.4 Hz, 2H), 1.34 (s, 4H), 0.55-0.42 (m, 4H),0.14 (t, J=5.6 Hz, 4H).

Chemical Synthesis Example 17bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)cyclohexane-1,4-dicarboxylate (Naltrexone-1,4-cyclohexyl-Naltrexone,Compound 15)

To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) indry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244mg, 2.0 mmol), 1,4-cyclohexanedicarboxylic acid (86 mg, 0.50 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg,2.00 mmol) and the mixture was stirred overnight. The mixture wasconcentrated onto 2 g reverse phase silica. Purification was performedby reverse phase automated chromatography (aqueous-MeCN gradient).Product containing fractions were combined and concentrated to give theproduct as an off-white solid (260 mg, 63%). Melting point: 145° C. HPLC(Method 3) retention time: 8.0 min, ESI MS+ Found, C₄₈H₅₅N₂O₁₀ ⁺ Mass:819.39 ¹H NMR (400 MHz, DMSO) δ 6.83 (dd, =8.2, 1.9 Hz, 2H), 6.72 (dd,J=8.3, 2.2 Hz, 2H), 5.15 (s, 2H), 4.93 (d, J=5.8 Hz, 2H), 3.17 (d, J=5.5Hz, 2H), 3.09 (s, 1H), 3.05 (s, 1H), 2.94 (s, 1H), 2.89 (dd, J=14.3, 5.0Hz, 2H), 2.72-2.59 (m, 3H), 2.57 (d, J=5.9 Hz, 1H), 2.38 (tt, J=11.0,6.2 Hz, 6H), 2.17-2.09 (m, 2H), 2.07 (s, 3H), 2.01-1.91 (m, 5H),1.89-1.75 (m, 4H), 1.58 (s, 1H), 1.45 (t, J=14.2 Hz, 2H), 1.30 (d,J=12.1 Hz, 2H), 0.87 (q, J=7.3 Hz, 2H), 0.55-0.43 (m, 4H), 0.19-0.09 (m,4H).

Chemical Synthesis Example 18bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)terephthalate (Naltrexone-1,4-terephthalate-Naltrexone. Compound 16)

To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) indry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244mg, 2.0 mmol), terephthalic acid (84 mg, 0.50 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg,2.00 mmol) and the mixture was stirred overnight. The mixture wasconcentrated onto 2 g reverse phase silica. Purification was performedby reverse phase automated chromatography (aqueous-MeCN gradient).Product containing fractions were combined and concentrated to give theproduct as an off-white solid (180 mg, 44%). Melting point: 240° C. HPLC(Method 3) retention time: 8.9 min, ESI MS+ Found, C₄₈H₄₉N₂O₁₀ ⁺ Mass:813.34 ¹H NMR (400 MHz, DMSO) δ 8.33 (d, J=2.2 Hz, 4H), 7.11-7.04 (m,2H), 6.81 (d, J=8.0 Hz, 2H), 5.18 (s, 2H), 4.97 (d, J=2.2 Hz, 2H),3.24-3.18 (m, 2H), 3.15 (s, 1H), 3.10 (s, 1H), 2.94 (d, J=2.2 Hz, 4H),2.75-2.60 (m, 2H), 2.42 (d, J=6.9 Hz, 6H), 2.18-2.05 (m, 4H), 2.01 (t,J=11.7 Hz, 2H), 1.83 (d, J=13.2 Hz, 2H), 1.50 (t, J=13.8 Hz, 2H), 1.37(d, J=12.5 Hz, 2H), 0.51 (d, J=8.1 Hz, 4H), 0.16 (d, J=5.0 Hz, 4H).

Chemical Synthesis Example 19bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)tetradecanedioate (Naltrexone-dodecane-Naltrexone, Compound 17)

To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) indry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244mg, 2.0 mmol), 1,12-dodecanedicarboxylic acid (129 mg, 0.50 mmol) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg,2.00 mmol) and the mixture was stirred overnight. The mixture wasconcentrated onto 2 g reverse phase silica. Purification was performedby reverse phase automated chromatography (aqueous-MeCN gradient).Product containing fractions were combined and concentrated to give theproduct as an off-white solid (248 mg, 55%). Melting point: 73° C. HPLC(Method 3) retention time: 12.9 min, ESI MS+ Found, C₅₄H₆₉N₂O₁₀ ⁺ Mass:905.50 ¹H NMR (400 MHz, DMSO) δ 6.81 (d, J=8.2 Hz, 21H), 6.71 (d, J=8.3Hz, 2H), 5.14 (s, 2H), 4.90 (s, 2H), 3.17 (d, J=5.6 Hz, 2H), 3.09 (s,1H), 3.04 (s, 1H), 2.97-2.85 (m, 2H), 2.67 (dd, J=12.0, 4.9 Hz, 2H),2.64-2.50 (m, 6H), 2.44-2.31 (m, 6H), 2.10 (dt, J=14.1, 3.2 Hz, 2H),1.96 (td, J=12.1, 3.8 Hz, 2H), 1.79 (dt, J 13.2, 4.2 Hz, 2H), 1.61 (p,J=7.3 Hz, 4H), 1.45 (td, J=13.9, 3.3 Hz, 2H), 1.39-1.21 (m, 18H),0.92-0.84 (m, 2H), 0.55-0.42 (m, 4H), 0.14 (p, J=6.4 Hz, 4H).

Chemical Synthesis Example 20bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)3-ethyl-3-methylpentanedioate (Naltrexone-3-ethyl-3-methylglutaricacid-Naltrexone, Compound 18)

To a stirred solution of naltrexone hydrochloride (378 mg, 1.00 mmol) indry DCM (50 mL) under nitrogen was added 4-(dimethylamino)pyridine (244mg, 2.0 mmol), 3-Ethyl-3-methylglutaric acid (87 mg, 0.50 mmol) andN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (383 mg,2.00 mmol) and the mixture was stirred overnight. The mixture wasconcentrated onto 2 g reverse phase silica. Purification was performedby reverse phase automated chromatography (aqueous-MeCN gradient).Product containing fractions were combined and concentrated to give theproduct as an off-white solid (157 mg, 38%). Melting point: 103° C. HPLC(Method 3) retention time: 8.8 min, ESI MS+ Found, C₄₈H₅₇N₂O₁₀ ⁺ Mass:821.40 ¹H NMR (400 MHz, DMSO) δ 6.96-6.89 (m, 2H), 6.83 (d, J=8.2 Hz,2H), 5.26 (s, 1H), 5.04 (d, J=2.3 Hz, 2H), 3.28 (d, J=5.6 Hz, 2H), 3.21(s, 1H), 3.16 (s, 1H), 3.08-2.96 (m, 3H), 2.80 (d, J=16.3 Hz, 6H), 2.71(dd, J=19.0, 5.9 Hz, 2H), 2.48 (s, 4H), 2.21 (dd, J=12.6, 2.5 Hz, 3H),2.07 (t, J=12.2 Hz, 2H), 1.90 (d, J=13.4 Hz, 2H), 1.74 (d, J=8.0 Hz,2H), 1.56 (t, J=13.9 Hz, 2H), 1.43 (d, J=12.7 Hz, 2H), 1.33 (s, 3H),1.25 (d, =J=2.3 Hz, 2H), 1.09-0.94 (m, 4H), 0.60 (d, J=8.1 Hz, 4H), 0.25(d, J=4.9 Hz, 4H).

Chemical Synthesis Example 21bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)hexane-1,6-diyl bis(carbonate) (Naltrexone-Hex-Naltrexone, Compound 19)

To a solution of 1,6-hexanediol (59 mg, 0.50 mmol), triethylamine (348uL, 2.5 mmol) and 4-(dimethylamino)pyridine (3.0 mg, 0.025 mmol) in DCM(10 mL) was added 4-nitrophenylchloroformate (222 mg, 1.1 mmol) and themixture stirred for 2 d. Naltrexone hydrochloride (567 mg, 1.5 mmol) wasadded and the mixture stirred overnight. The mixture was concentratedonto 2 g reverse phase silica. Purification was performed by reversephase automated chromatography (aqueous-MeCN gradient). Productcontaining fractions were combined and concentrated to give the productas an off-white solid (85 mg, 20%). Melting point: 102° C. HPLC (Method3) retention time: 8.3 min, ESI MS+ Found, C₄₈H₅₇N₂O₁₂ ⁺ Mass: 853.39 ¹HNMR (400 MHz, DMSO) δ 6.82 (d, J=8.2 Hz, 2H), 6.71 (d, J=8.2 Hz, 2H),5.14 (s, 2H), 4.91 (s, 2H), 4.18 (m, 4H), 3.17 (d, J=5.6 Hz, 2H), 3.09(s, 2H), 3.04 (s, 2H), 2.97-2.84 (m, 4H), 2.67 (dd, J=12.0, 5.0 Hz, 2H),2.64-2.51 (m, 8H), 2.44-2.31 (m, 6H), 2.15-2.05 (m, 4H), 1.95 (td,J=12.1, 3.8 Hz, 2H), 1.79 (dd, J=13.6, 4.8 Hz, 2H), 1.63 (p, J=7.2 Hz,4H), 1.46 (dd, J=14.0, 3.4 Hz, 2H), 1.34 (s, 2H), 0.55-0.42 (m, 2H).

Chemical Synthesis Example 22 cyclohexane-1,4-diylbis(methylene)bis((4R,4aS,7aR,12bS)-3-(cyclopropylmethyl)-4a-hydroxy-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)bis(carbonate) (Naltrexone-CDM-Naltrexone, Compound 20)

To a solution of 1,4-cyclohexanedimethanol (72 mg, 0.50 mmol),triethylamine (348 uL, 2.5 mmol) and 4-(dimethylamino)pyridine (3.0 mg,0.025 mmol) in DCM (10 mL) was added 4-nitrophenylchloroformate (222 mg,1.1 mmol) and the mixture stirred for 2 d. Naltrexone hydrochloride (567mg, 1.5 mmol) was added and the mixture stirred overnight. The mixturewas concentrated onto 2 g reverse phase silica. Purification wasperformed by reverse phase automated chromatography (aqueous-MeCNgradient). Product containing fractions were combined and concentratedto give the product as an off-white solid (90 mg, 20%). Melting point:131° C. HPLC (Method 3) retention time: 8.8 min, ESI MS+ Found,C₅₀H₅N₂O₁₂ ⁺ Mass: 879.41 ¹H NMR (400 MHz, DMSO) δ 6.81 (d, J=8.2 Hz,2H), 6.70 (d, J=8.2 Hz, 2H), 5.14 (s, 2H), 4.91 (s, 2H), 3.98-4.17 (m,4H) 3.07-3.22 (m, 6H) 2.86-3.02 (m, 4H) 2.52-2.65 (m, 4H) 2.32-2.45 (m,2H) 2.10 (br d, J=14.03 Hz, 2H) 1.95 (td, J=12.06, 3.51 Hz, 2H) 1.76 (brd, J=8.11 Hz, 6H) 1.64 (br s, 2H) 1.37-1.56 (m, 4H) 1.28 (br d, J=10.74Hz, 2H) 1.03 (br t, J=8.33 Hz, 2H), 0.87 (q, J=7.3 Hz, 2H), 0.55-0.43(m, 4H), 0.19-0.09 (m, 4H).

Chemical Synthesis Example 23bis((4R,4aR,7aR,12bS)-3-methyl-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-yl)adipate (Hydromorphone-Adip-Hydromorphone, Compound 21)

To a fine suspension of hydromorphone free base (456 mg, 1.60 mmol) inanhydrous THF (11.5 mL) was added 60% sodium hydride in mineral oil (64mg, 1.60 mmol) portionwise and the mixture was stirred for 10 min undernitrogen. Adipoyl chloride (139 mg, 111 μL, 0.76 mmol) was added andstirring was continued overnight under nitrogen. The solution wasquenched with saturated aqueous ammonium chloride (50 mL) and extractedwith dichloromethane (3×40 mL). The combined organic layers were washedwith saturated brine (50 mL), dried (MgSO4) and concentrated to give awhite solid (550 mg). Purification was performed by reverse phaseautomated chromatography (aqueous HCl-MeCN gradient). Product containingfractions were combined, concentrated to ˜50% volume, poured intosaturated aqueous sodium bicarbonate (50 mL) and extracted withdichloromethane (4×50 mL). The combined organic layers were washed withsaturated brine (50 mL), dried (MgSO₄) and concentrated to give a whiteglassy solid (408 mg) containing ˜15% hydromorphone. A furtherpurification was performed using reverse phase automated chromatography(aqueous HCl-MeCN gradient). Product containing fractions were combined,concentrated to ˜50% volume, poured into saturated aqueous sodiumbicarbonate (25 mL) and extracted with dichloromethane (3×20 mL). Thecombined organic layers were washed with saturated brine (20 mL), dried(MgSO₄) and concentrated and concentrated to give the product as a whiteglassy solid (230 mg, 44%). Melting point: 112° C. HPLC (Method 3)retention time: 8.1 min, ESI MS+ Found, C₄₀H₄₅N₂O₈ ⁺ Mass: 681.32 ¹H NMR(400 MHz, DMSO-d6) δ 6.82 (d, J=8.0 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H),4.97 (s, 2H), 3.14 (d, J=5.6 Hz, 2H), 2.98 (td, J=14.3, 5.0 Hz, 2H),2.54 (m, 10H), 2.32 (m, 8H), 2.17 (dt, J=12.6, 2.4 Hz, 2H), 2.03 (td,J=12.1, 3.8 Hz, 2H), 1.95 (td, J=12.1, 3.8 Hz, 2H), 1.74 (m, 6H), 1.48(td, J=14.0, 3.4 Hz, 2H), 1.00 (m, 2H).

Chemical Synthesis Example 24bis((4R,4aR,7S,7aR,12bS)-9-methoxy-3-methyl-2,3,4,4a,7,7a-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-yl)adipate (Codeine-Adip-Codeine, Compound 22)

To a stirred solution of codeine free base (440 mg, 1.47 mmol) inanhydrous DMF (50 mL) was added adipic acid (102 mg, 0.70 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.55 g,2.87 mmol) and 4-(dimethylamino)pyridine (385 mg, 3.15 mmol) and themixture was stirred overnight. The resulting solution was quenched withsaturated aqueous ammonium chloride (50 mL) and extracted withdichloromethane (4×50 mL). The combined organic layers were washed withwater (4×50 mL), saturated brine (50 mL), dried (MgSO4) and concentratedto give a white solid. Purification was performed by reverse phaseautomated chromatography (aqueous HCl-MeCN gradient). Product containingfractions were combined, concentrated to approximately 50% volume,poured into saturated aqueous sodium bicarbonate (100 mL) and extractedwith dichloromethane (3×80 mL). The combined organic layers were washedwith saturated brine (80 mL), dried (MgSO4) and concentrated to give thedesired product as a white solid which was further purified by using anautomated chromatography system under normal phase conditions (silicacolumn, gradient of 2→30% methanol in dichloromethane) with detection at254 nm to give the product (280 mg, 56%) as a white solid. Meltingpoint: 209° C. HPLC (Method 3) retention time: 8.3 min, ESI MS+ Found,C₄₂H₄₉N₂O₈ ⁺ Mass: 709.35 ¹H NMR (400 MHz, CDCl₃) δ 6.58 (d, J=8.0 Hz,2H), 6.47 (d, J=8.0 Hz, 2H), 5.56 (m, 2H), 5.35 (m, 2H), 5.10 (m, 2H),5.01 (d, J=8.0 Hz, 2H), 3.76 (s, 6H), 3.28 (m, 2H), 2.97 (d, J=12.0 Hz,2H), 2.68 (m, 2H), 2.54 (m, 2H), 2.41 (m, 10H), 2.25 (m, 4H), 2.01 (m,2H), 1.77 (m, 2H), 1.71 (m, 4H).

III. Formation and Evaluation of Processable Conjugates Example 1: HeatProcessing of Compounds

Compounds that were collected as stable powders and/or gums wereinvestigated for pellet formation by heat molding. Compounds wereprocessed at a temperature ˜10-30° C. above their corresponding thermaltransitions (glass transition temperature (Tg) for gums or amorphouspowders or melting point (Tm) for crystalline powders) and pressed intoa cylindrical mold of ˜1 mm in height×1 mm in diameter. Light microscopywas used to capture images of the heat-formed pellets. Temperatures usedto achieve a melt for heat molding were in a range from 70° C. to 220°C.

Compound 3 and Compound 5 successfully formed glassy, mostly transparentpellets and had mechanical properties that allowed them to be easilyhandled without breaking. These pellets had the appropriate processingproperties to be tested as articles for drug delivery applications.Compound 8 formed opaque yellow-tinted pellets that could be handled andassessed for drug release. Compound 2 formed a viscous liquid uponmelting and flowed into the heat-mold template but displayed a softenedstate under ambient conditions and deformed during the process ofremoval from the mold. The recovered form was soft and tacky and couldnot be easily handled.

Compounds 9 and 11-22 successfully formed a (e.g., glassy, mostlytransparent) pellet and provided mechanical properties that allowed thepellets to be handled without breaking. These pellets had theappropriate processing properties to be tested as articles for drugdelivery applications. Compound 10 was yellow upon heating and didn'tform a viscous liquid that could be pressed into a pellet. The recoveredform of Compound 10 was brittle and did not have mechanical propertiesthat allowed the pellet to be handled without breaking.

Example 2: Solvent Processing

Compound 9 was formed into a thin film coating on a polymer surface bysolvent casting. Compound 9 was dissolved in acetone at 100 mg/ml and 10μl of the solution was cast onto a Dacron coupon and left to air dry atroom temperature overnight. Images of the thin, transparent coating werecaptured by light microscopy.

Compound 3 and Compound 5 were formed into a thin film coating on apolymer surface by solvent casting. Compounds were dissolved in acetoneat 100 mg/ml and 10 μl of the solution was cast onto a Dacron coupon andleft to air dry at room temperature overnight. Images of the thin,transparent coating were captured by light microscopy.

IV. Drug Release Evaluation Example 1: Drug Release from Pellets

Drug release from heat-molded pellets of the compounds were assessed inphosphate buffered saline (PBS). Heat-molded pellets were placed in 20ml glass vials and 2 ml of release buffer was added. Samples wereincubated at 37° C. with constant agitation at 115 rpm. Release bufferwas sampled and fully replaced with 2 ml of fresh buffer on days 1, 3,7, 10, and 14. Samples were analyzed by high performance liquidchromatography (HPLC) to quantify drug products. Cumulative release wascalculated as a percentage of total mass of starting pellets and wasplotted over time.

Heat molded pellets of Compound 3, Compound 5, and Compound 8 were thenplaced in 20 mL glass vials and 4 mL of release buffer (phosphatebuffered saline, PBS) was added. Samples were incubated at 37° C. on ashaker rotating at 115 rpm. Observations made after a 1-day incubationshow mechanical collapse for Compound 3 and Compound 5 pellets under thetest conditions and the pellet shape changed to a clear gel (Compound 3)or fragmented entirely to opaque particulates (Compound 5). Drug releasefrom Compound 8 was assessed by HPLC from PBS release buffer weekly for8 weeks with full buffer change at each time point. Minimal drug releasewas observed over the time period investigated.

Example 2: Drug Release from a Polymer Surface Coated

Compound-coated Dacron films were placed into 20 mL vials, 2 mL fetalbovine serum (FBS) was added, and the samples were incubated at 37 C. Atday 1, 3, and 7, the FBS was removed, proteins were precipitated withthe addition of MeCN (2:1 ratio), and the suspension was transferred toa centrifuge tube. The tubes were centrifuged at 10,000 rpm for 6 minand the supernatant was analyzed by HPLC to quantify the releaseproducts. A fresh 2 mL of FBS was added and the sample was incubation at37° C. until the next timepoint.

We claim:
 1. An article comprising a compound having a structure ofFormula (II-A):D1-L-D2  (II-A) wherein: D1 is a first radical; D2 is a second radical;L is a (e.g., hydrolyzable) linker covalently linking D1 to D2, or apharmaceutically salt or solvate thereof, wherein the first and secondradicals are non-steroidal.
 2. The compound of any one of the precedingclaims, wherein D1 and/or D2 are attached to the linker through ahydroxyl radical, an amine radical, an amide radial, a carboxylateradical, or a thiol radical.
 3. The compound of any one of the precedingclaims, wherein D1 and/or D2 are attached to the linker through ahydroxyl radical, an amine radical, or a carboxylate radical.
 4. Thecompound of claim 3, wherein the first radical and the second radicalare each independently selected from a nonsteroidal anti-inflammatorydrug (NSAID) (e.g., pranoprofen, bromfenac, and indoprofen), a CNS agent(e.g., an analgesic agent, an anti-psychotic agent (e.g., haloperidol),an anti-depressive agent, an anti-histamine, an anti-convulsant (e.g.,L-DOPA)), a rho kinase (ROCK) inhibitor (e.g., ripasudil and fasudil),an anthraquinone (e.g., diacerein), an anti-cancer agent (e.g.,podophyllotoxin, SN-38, and melphalan), an anti-viral agent (e.g.,trifluridine and podophyllotoxin), an anti-oxidant (e.g., ferulic acidand kaempferol), a muscarinic antagonist, an anti-microbial agent (e.g.,cefazolin and tedizolid), or an anti-coagulant (e.g., warfarin) in theirfree form.
 5. The compound of any one of the preceding claims, whereinat least one of the first radical or the second radical is a solid(e.g., at a temperature of less than or equal to 30° C.) in their freeform.
 6. The compound of any one of the preceding claims, wherein thefirst radical and the second radical are each a solid (e.g., at atemperature of less than or equal to 30° C.) in their free form.
 7. Thecompound of any one of the preceding claims, having the structure ofFormula (II-B):

wherein: L is a linker, or a pharmaceutically acceptable salt thereof.8. The compound of any one of the preceding claims, having the structureof Formula (II-C):

wherein: L is a linker, or a pharmaceutically acceptable salt thereof.9. The compound of any one of the preceding claims, having the structureof Formula (II-D):

wherein: R^(m) and R^(m)′ are each independently H or optionallysubstituted alkyl; R^(n) and R^(n)′ are each independently H oroptionally substituted alkyl; and L is a linker, or a pharmaceuticallyacceptable salt thereof.
 10. The compound of any one of the precedingclaims, having the structure of Formula (II-E):

wherein: R^(m) and R^(m)′ are each independently H or optionallysubstituted alkyl; R^(n) and R^(n)′ are each independently H oroptionally substituted alkyl; R^(o) and R^(o)′ are each independently Hor optionally substituted alkyl; and L is a linker, or apharmaceutically acceptable salt thereof.
 11. The compound of any one ofthe preceding claims, having the structure of Formula (II-F):

wherein: L is a linker, or a pharmaceutically acceptable salt thereof.12. The compound of any one of claims 7-10, wherein any one of R^(m),R^(n), or R^(o) is adjoined to any one of R^(m)′, R^(n)′, or R^(o)′ bythe linker.
 13. The compound of any one of claims 7-11, wherein R^(m) isadjoined to R^(m)′ by the linker.
 14. The compound of any one of claims7-11, wherein R^(n) is adjoined to R^(n)′ by the linker.
 15. Thecompound of any one of claims 10-11, wherein R^(o) is adjoined to R^(o)′by the linker.
 16. The compound of any one of the preceding claims,wherein the linker is a hydrolyzable linker.
 17. The compound of any oneof the preceding claims, wherein the hydrolyzable linker comprises oneor more hydrolyzable group.
 18. The compound of any one of the precedingclaims, wherein the linker is alkyl (e.g., saturated alkyl orunsaturated alkyl), heteroalkyl, or alkoxy, wherein the alkyl,heteroalkyl, or alkoxy is optionally substituted.
 19. The compound ofany one of the preceding claims, wherein the alkyl, heteroalkyl, oralkoxy are each independently substituted with one or more groups, eachgroup being independently selected from oxo, —O—, —S—, silicone, amino,alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl,wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl are optionally substituted.
 20. The compound of any one ofthe preceding claims, wherein the linker comprises one or more linkergroups, each linker group being independently selected from oxo, —O—,—S—, optionally substituted alkylene (e.g., alkenyl, alkynyl, branched(e.g., polypropylene), haloalkyl), optionally substituted heteroalkylene(e.g, polyTHF), and optionally substituted cycloalkylene.
 21. Thecompound of any one of the preceding claims, wherein the linkercomprises one or more linker groups, each linker group beingindependently selected from alkyl, alkoxy, and cycloalkyl, wherein thealkyl, alkoxy, or cycloalkyl are optionally substituted.
 22. Thecompound of any one of the preceding claims, wherein the linkercomprises one or more linker groups selected from oxo, —O—, —S—,unsubstituted alkylene, (CH₂CH₂)_(n), (CHCH)_(n), O(CH₂CH₂O)_(n),(CH₂CH₂O)_(n), and (CH(CH₃)C(═O)O)_(n), wherein n is 1-20.
 23. Thecompound of any one of any one of the preceding claims, wherein thelinker comprises one or more linker group selected from oxo,unsubstituted alkylene, (CH₂CH₂)_(n), (CHCH)_(n), O(CH₂CH₂O)_(n),(CH₂CH₂O)_(n), (CH(CH₃)C(═O)O)_(n), or(CH₂CH₂)_(n)C═O(CH(CH₃)C(═O)O)_(n), wherein n is 1-20.
 24. The compoundof any one of claims 1-21, wherein the linker is alkyl (alkylene)substituted with one or more groups selected from —OH, halo, oxo, alkyl,heteroalkyl, cycloalkyl, and heterocycloalkyl.
 25. The compound of anyone of claims 1-21, wherein the linker is unsubstituted alkyl(alkylene).
 26. The compound of any one of claims 1-21, wherein thelinker is heteroalkyl (heteroalkylene) substituted with one or moregroups selected from halo or alkyl.
 27. The compound of any one ofclaims 1-21, wherein the linker is unsubstituted heteroalkyl(heteroalkylene).
 28. The compound of any one of the preceding claims,wherein the linker is selected from the group consisting of:—(CR₂)_(y)—, —(C═O)(CR₂)_(y)(C═O)—, —O(CR₂)_(y)O—,—(C═O)O(CR₂)_(y)O(C═O)—, —O(CR₂)_(y)—, —(CR₂)_(y)O—, and—O(CH₂CH₂O)_(y)—, wherein y is 1-10 and each R is independently selectedfrom the group consisting of H, halogen, alkyl, or is taken togetherwith another R to form an optionally substituted cycloalkyl.
 29. Thecompound of any one of the preceding claims, wherein the linker ishydrolyzed in a buffered solution.
 30. The compound of any one of thepreceding claims, wherein the linker is hydrolyzed by an enzyme.
 31. Thecompound of claim 29, wherein the enzyme is a hydrolase (e.g., aprotease or an esterase).
 32. A compound selected from the groupconsisting of:

or any pharmaceutically acceptable salt thereof.
 33. The compound of anyone of the preceding claims, wherein the compound is processable (e.g.,into an article or the amorphous state).
 34. The compound of any one ofthe preceding claims, wherein the compound is a solid (e.g., has amelting point (e.g., T_(m) or T_(g)) of at least 37° C.).
 35. Thecompound of any one of the preceding claims, wherein the compound is acrystalline solid, a film, a glass, or an amorphous solid (e.g., at atemperature of at least 37° C.).
 36. The compound of any one of thepreceding claims, wherein the compound has crystallinity of at most 15%(e.g., determined by PXRD, DSC, or polarized light microscopy).
 37. Thecompound of any one of the preceding claims, wherein the compound issubstantially not crystalline (e.g., determined by PXRD, DSC, orpolarized light microscopy).
 38. The compound of any one of thepreceding claims, wherein the compound is amorphous (e.g., determined byPXRD, DSC, or polarized light microscopy).
 39. The compound of any oneof the preceding claims, wherein the thermal melting point (T_(m)) isgreater than or equal to the glass transition temperature (T_(g)). 40.The compound of any one of the preceding claims, wherein the compoundhas a melting point of at least 37° C.
 41. The compound of anyone of thepreceding claims, wherein the compound has a melting point of at least100° C.
 42. The compound of any one of the preceding claims, whereineither one or both of the first and/or second radicals are released(e.g., in their free form), the release being sustained release and/orextended release.
 43. The compound of any one of the preceding claims,wherein either one or both of the first and/or second radicals beingreleased (e.g., in their free form) for at least 14 days (e.g., insolution, buffer solution, serum, biological environment, in vivo, orthe like).
 44. A pharmaceutical implant or coating comprising a compoundof any one of the preceding claims, or a pharmaceutically acceptablesalt thereof.
 45. The pharmaceutical implant or coating of claim 43,wherein the implant or coating comprises at least 50 wt. % (at least 60wt. %, at least 70 wt. %, at least 80 wt. %, at least 90 wt. %, at least95 wt. %, at least 98 wt. %, or the like) of the compound and/orpharmaceutically acceptable salt thereof.
 46. The pharmaceutical implantor coating according to claim 43 or 44, wherein the implant or coatingundergoes surface erosion to release the compound, the first radical,and/or the second radical.
 47. The pharmaceutical implant or coating anyone of claims 43-45, wherein the first radical and the second radicalare released from the pharmaceutical implant or coating at nearzero-order in a buffered solution or in vivo.
 48. The pharmaceuticalimplant or coating of any one of claims 43-46, wherein the first radicaland the second radical are released from the pharmaceutical implant orcoating at 37° C. in 100% bovine serum or at 37° C. in phosphatebuffered saline (PBS) at a rate such that t₁₀ is greater than or equalto 1/10 of t₅₀.
 49. A pharmaceutical composition comprising a compoundof any one of the preceding claims, or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable excipient.50. The implant, article, or composition of any one of the precedingclaims, wherein the pharmaceutical composition is suitable foradministration to an individual in need thereof.
 51. A method fortreating a disease or disorder (e.g., or the symptoms thereof) in anindividual in need thereof, the method comprising implanting thearticle, implant, or composition of any one of the preceding claims intothe individual.
 52. The method of claim 50, wherein the disease ordisorder is an acute or a chronic disease or disorder.
 53. The method ofany one of claim 50 or 51, wherein the disease or disorder is selectedfrom a neurodegenerative disease or disorder (e.g., Parkinson'sDisease), pain, an ocular disease or disorder (e.g., glaucoma), asthma,constipation, anxiety, inflammation, psychosis, convulsion, epilepsy,infection (e.g., microbial, bacterial, viral, fungal), cancer, diabetes,osteoporosis, arthritis, and depression.
 54. The method of any one ofclaims 50-52, wherein removal of the article or implant from theindividual administered the article or implant is not required (e.g.,because the implant is completely or almost completely (e.g., bio- orphysiologically) degraded or degradable (e.g., at least 80 wt. %, atleast 85 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %,at least 99 wt. %, or the like)).
 55. The method of any one of claims50-52, wherein the article or implant is not removed (e.g., because theimplant is completely or almost completely (e.g., bio- orphysiologically) degraded or degradable (e.g., at least 80 wt. %, atleast 85 wt. %, at least 90 wt. %, at least 95 wt. %, at least 98 wt. %,at least 99 wt. %, or the like)) from an individual administered thearticle or implant.